Drugs and Human Performance Fact Sheets - Washington State Patrol

NATIONAL HIGHWAY TRAFFIC SAFETY ADMINISTRATION
Drugs and Human
Performance Fact Sheets

Technical Report Documentation Page
1. Report No. 2. Government Accession No. 3. Recipient's Catalog No.
DOT HS 809 725
4. Title and Subtitle
Drugs and Human Performance Fact Sheets
5. Report Date
April 2004
6. Performing Organization Code
7. Author(s)
COUPER, Fiona J. and LOGAN, Barry K
8. Performing Organization Report No.
9. Performing Organization Name and Address
10. Work Unit No. (TRAIS)
Washington State PatrolForensic Laboratory Services Bureau
2203 Airport Way S., Seattle, WA 98134 11. Contract or Grant No.
12. Sponsoring Agency Name and Address’
National Highway Traffic Safety Administration
400 Seventh St., SW.
Washington, DC 20590
13. Type of Report and Period Covered
Final Report;
August 2000-March 2004
14. Sponsoring Agency Code
15. Supplementary Notes
The following toxicologists made significant contributions to both the drafting and review of the Fact Sheets: Michael
Corbett Ph.D., Laurel Farrell MS., Marilyn Huestis Ph.D., Wayne Jeffrey MS, and Jan Raemakers, Ph.D. James F.Frank
Ph.D. served as the NHTSA Contracting Officer's Technical Representative.
16. Abstract
A panel of international experts on drug-impaired driving met in Seattle during August 2000 to review developments in the
field of drugs and human performance over the last 10 years; to identify the specific effects that both illicit and prescription
drugs have on driving; and to develop guidance for others when dealing with drug-impaired driving problems. Delegates
represented the fields of psychopharmacology, behavioral psychology, drug chemistry, forensic toxicology, medicine, and
law enforcement experts trained in the recognition of drug effects on drivers in the field.
These Fact Sheets represent the conclusions of the Panel and include the state of current scientific knowledge in the area of
drugs and human performance for the 16 drugs selected for evaluation. The selected drugs include over-the-counter
medications such as dextromethorphan and diphenhydramine; prescription medications such as carisoprodol, diazepam and
zolpidem; and abused and/or illegal drugs such as cocaine, GHB, ketamine, LSD, marijuana, methadone, methamphetamine,
MDMA, morphine, PCP and toluene.
Keyword continuation: illicit and licit drugs and traffic safety, drugs and driving, drug-impaired driving.
17. Key Words
18. Distribution Statement
Carisoprodol, cocaine, dextromethorphan, diazepam,
diphenhydramine, GHB,ketamine, LSD,
marijuana,methadone, methamphetamine,MDMA,
morphine, PCP, toluene, zolpidem,
19. Security Classif. (of this report)
20. Security Classif. (of this page)
none
none
Form DOT F 1700.7 (8-72) Reproduction of completed page authorized
21. No. of Pages
100
22. Price

Table of Contents
Page
Introduction………………………………………………………. 3
Cannabis/Marijuana……………………………………………… 7
Carisoprodol (and Meprobamate)………………………………... 13
Cocaine…………………………………………………………… 19
Dextromethorphan……………………………………………….. 25
Diazepam………………………………………………………… 29
Diphenhydramine………………………………………………… 35
Gamma-Hydroxybutyrate (GHB, GBL, and 1,4-BD)……………. 39
Ketamine………………………………………………………….. 45
Lysergic acid diethylamide (LSD)………………………………... 51
Methadone………………………………………………………… 55
Methamphetamine (and Amphetamine)…………………………... 61
Methylenedioxymethamphetamine (MDMA, Ecstasy)…………… 67
Morphine (and Heroin)……………………………………………. 73
Phencyclidine (PCP)………………………………………………. 79
Toluene……………………………………………………………. 85
Zolpidem (and Zaleplon, Zopiclone)……………………………… 91
Biographical Sketches of Lead Authors and Main Contributors….. 97

Introduction
The use of psychoactive drugs followed by driving has been an issue of continual concern
to law enforcement officers, physicians, attorneys, forensic toxicologists and traffic
safety professionals in the U.S. and throughout the world. At issue are methods for
identifying the impaired driver on the road, the assessment and documentation of the
impairment they display, the availability of appropriate chemical tests, and the
interpretation of the subsequent results. A panel of international experts on drug-related
driving issues met to review developments in the field of drugs and human performance
over the last 10 years; to identify the specific effects that both illicit and prescription
drugs have on driving; and to develop guidance for others when dealing with drugimpaired
driving problems.
This publication is based on the deliberations of the International Consultative Panel on
Drugs and Driving Impairment held in Seattle, WA in August 2000. This meeting was
sponsored by the National Safety Council, Committee on Alcohol and other Drugs; the
State of Washington Traffic Safety Commission; and the National Highway Traffic
Safety Administration. Delegates represented the fields of psychopharmacology,
behavioral psychology, drug chemistry, forensic toxicology, medicine, and law
enforcement experts trained in the recognition of drug effects on drivers in the field. The
Fact Sheets reflect the conclusions of the Panel and have been designed to provide
practical guidance to toxicologists, pharmacologists, law enforcement officers, attorneys
and the general public on issues related to drug impaired driving.
Sixteen drugs were selected for review and include over-the-counter medications,
prescription drugs, and illicit and/or abused drugs. The selected drugs are
cannabis/marijuana, carisoprodol, cocaine, dextromethorphan, diazepam,
diphenhydramine, gamma-hydroxybutyrate, ketamine, lysergic acid diethylamide,
methadone, methamphetamine/amphetamine, methylenedioxymethamphetmaine,
morphine/heroin, phencyclidine, toluene, and zolpidem.
The Fact Sheets are based on the state of current scientific knowledge and represent the
conclusions of the panel. They have been designed to provide practical guidance to
toxicologists, pharmacologists, law enforcement officers, attorneys and the general public
to use in the evaluation of future cases. Each individual drug Fact Sheet covers
information regarding drug chemistry, usage and dosage information, pharmacology,
drug effects, effects on driving, drug evaluation and classification (DEC), and the panel’s
assessment of driving risks. A list of key references and recommended reading is also
provided for each drug. Readers are encouraged to use the Fact Sheets in connection with
the other cited impaired driving-related texts.
The information provided is uniform for all the Fact Sheets and provides details on the
physical description of the drug, synonyms, and pharmaceutical or illicit sources; medical
and recreational uses, recommended and abused doses, typical routes of administration,
and potency and purity; mechanism of drug action and major receptor sites; drug
absorption, distribution, metabolism and elimination data; blood and urine
concentrations; psychological and physiological effects, and drug interactions; drug
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effects on psychomotor performance effects; driving simulator and epidemiology studies;
and drug recognition evaluation profiles. Each Fact Sheet concludes with general
statements about the drugs’ ability to impair driving performance. The authors strongly
believe that all the above information needs to be taken into account when evaluating a
drug.
Case interpretation can be complicated by a number of factors and one of the main
limitations of the Fact Sheets is that they primarily relate to single drug use. Other factors
which influence the risk of effects on driving for any drug include the dose, the dosage
frequency, acute and residual effects, chronic administration, route of administration, the
concentration of the drug at the site of action, idiosyncrasies of metabolism, drug
tolerance or hypersensitivity, and the combined effects of the drug with other drugs or
alcohol, to name but a few.
Individual Fact Sheets
Cannabis/Marijuana
Carisoprodol (and Meprobamate)
Cocaine
Dextromethorphan
Diazepam
Diphenhydramine
Gamma-Hydroxybutyrate (GHB, GBL, and 1,4-BD)
Ketamine
Lysergic acid diethylamide (LSD)
Methadone
Methamphetamine (and Amphetamine)
Methylenedioxymethamphetamine (MDMA, Ecstasy)
Morphine (and Heroin)
Phencyclidine (PCP)
Toluene
Zolpidem (and Zaleplon, Zopiclone)
Lead Authors:
Fiona Couper, Ph.D. and Barry Logan, Ph.D.
Main contributors:
Michael J Corbett, Ph.D., Laurel Farrell, BS, Marilyn Huestis Ph.D., Wayne Jeffrey, BS,
Jan Raemakers Ph.D.
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Other delegates to the consensus conference:
Marcelline Burns, Ph.D.; Yale Caplan, Ph.D.; Dennis Crouch, BS, MBA; Johann De
Gier, Ph.D.; Olaf Drummer Ph.D.; Kurt Dubowski, Ph.D.; Robert Forney Jr., Ph.D.;
Bernd Freidel, M.D.; Manfred Moeller, Ph.D.; Thomas Page, BA; Lionel Raymon,
Pharm.D., Ph.D., Wim Riedel, Ph.D.; Laurent Rivier, Ph.D.; Annemiek Vermeeren,
Ph.D. and H. Chip Walls BS. Other participants included James F. Frank, Ph.D. from the
NHTSA Office of Research & Technology; Sgt. Steven Johnson of the Washington State
Patrol; Capt. Chuck Hayes of the Oregon State Patrol; and Sgt. Douglas Paquette of the
New York State Police.
Disclaimer
The information contained in the Drugs and Human Performance Fact Sheets represents
the views of the contributors and not necessarily those of their place of employment or
the National Highway Traffic Safety Administration.
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Cannabis / Marijuana (∆ 9 -Tetrahydrocannabinol, THC)
Marijuana is a green or gray mixture of dried shredded flowers and leaves of the hemp
plant Cannabis sativa. Hashish consists of resinous secretions of the cannabis plant.
Dronabinol (synthetic THC) is a light yellow resinous oil.
Synonyms: Cannabis, marijuana, pot, reefer, buds, grass, weed, dope, ganja, herb,
boom, gangster, Mary Jane, sinsemilla, shit, joint, hash, hash oil, blow, blunt, green,
kilobricks, Thai sticks; Marinol®
Source: Cannabis contains chemicals called cannabinoids, including cannabinol,
cannabidiol, cannabinolidic acids, cannabigerol, cannabichromene, and several isomers
of tetrahydrocannabinol (THC). One of these isomers, ∆ 9 -THC, is believed to be
responsible for most of the characteristic psychoactive effects of cannabis. Marijuana
refers to the leaves and flowering tops of the cannabis plant; the buds are often preferred
because of their higher THC content. Hashish consists of the THC-rich resinous
secretions of the plant, which are collected, dried, compressed and smoked. Hashish oil is
produced by extracting the cannabinoids from plant material with a solvent. In the U. S. ,
marijuana, hashish and hashish oil are Schedule I controlled substances. Dronabinol
(Marinol®) is a Schedule III controlled substance and is available in strengths of 2.5, 5 or
10 mg in round, soft gelatin capsules.
Drug Class: Cannabis/Marijuana: spectrum of behavioral effects is unique, preventing
classification of the drug as a stimulant, sedative, tranquilizer, or hallucinogen.
Dronabinol: appetite stimulant, antiemetic.
Medical and Recreational Uses: Medicinal: Indicated for the treatment of anorexia
associated with weight loss in patients with AIDS, and to treat mild to moderate nausea
and vomiting associated with cancer chemotherapy. Recreational: Marijuana is used for
its mood altering effects, euphoria, and relaxation. Marijuana is the most commonly used
illicit drug throughout the world.
Potency, Purity and Dose: THC is the major psychoactive constituent of cannabis.
Potency is dependent on THC concentration and is usually expressed as %THC per dry
weight of material. Average THC concentration in marijuana is 1-5%, hashish 5-15%,
and hashish oil ≥ 20%. The form of marijuana known as sinsemilla is derived from the
unpollinated female cannabis plant and is preferred for its high THC content (up to 17%
THC). Recreational doses are highly variable and users often titer their own dose. A
single intake of smoke from a pipe or joint is called a hit (approximately 1/20th of a
gram). The lower the potency or THC content the more hits are needed to achieve the
desired effects; 1-3 hits of high potency sinsemilla is typically enough to produce the
desired effects. In terms of its psychoactive effect, a drop or two of hash oil on a cigarette
is equal to a single “joint” of marijuana. Medicinally, the initial starting dose of
Marinol® is 2.5 mg, twice daily.
Route of Administration: Marijuana is usually smoked as a cigarette (‘joint’) or in a
pipe or bong. Hollowed out cigars packed with marijuana are also common and are called
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`. Joints and blunts are often laced with adulterants including PCP or crack cocaine.
Joints can also be dipped in liquid PCP or in codeine cough syrup. Marijuana is also
orally ingested.
Pharmacodynamics: THC binds to cannabinoid receptors and interferes with important
endogenous cannabinoid neurotransmitter systems. Receptor distribution correlates with
brain areas involved in physiological, psychomotor and cognitive effects.
Correspondingly, THC produces alterations in motor behavior, perception, cognition,
memory, learning, endocrine function, food intake, and regulation of body temperature.
Pharmacokinetics: Absorption is slower following the oral route of administration with
lower, more delayed peak THC levels. Bioavailability is reduced following oral ingestion
due to extensive first pass metabolism. Smoking marijuana results in rapid absorption
with peak THC plasma concentrations occurring prior to the end of smoking.
Concentrations vary depending on the potency of marijuana and the manner in which the
drug is smoked, however, peak plasma concentrations of 100-200 ng/mL are routinely
encountered. Plasma THC concentrations generally fall below 5 ng/mL less than 3 hours
after smoking. THC is highly lipid soluble, and plasma and urinary elimination half-lives
are best estimated at 3-4 days, where the rate-limiting step is the slow redistribution to
plasma of THC sequestered in the tissues. Shorter half-lives are generally reported due to
limited collection intervals and less sensitive analytical methods. Plasma THC
concentrations in occasional users rapidly fall below limits of quantitation within 8 to 12
h. THC is rapidly and extensively metabolized with very little THC being excreted
unchanged from the body. THC is primarily metabolized to 11-hydroxy-THC which has
equipotent psychoactivity. The 11-hydroxy-THC is then rapidly metabolized to the 11-
nor-9-carboxy-THC (THC-COOH) which is not psychoactive. A majority of THC is
excreted via the feces (~65%) with approximately 30% of the THC being eliminated in
the urine as conjugated glucuronic acids and free THC hydroxylated metabolites.
Molecular Interactions / Receptor Chemistry: THC is metabolized via cytochrome
P450 2C9, 2C11, and 3A isoenzymes. Potential inhibitors of these isoenzymes could
decrease the rate of THC elimination if administered concurrently, while potential
inducers could increase the rate of elimination.
Blood to Plasma Concentration Ratio: 0.55
Interpretation of Blood Concentrations: It is difficult to establish a relationship
between a person's THC blood or plasma concentration and performance impairing
effects. Concentrations of parent drug and metabolite are very dependent on pattern of
use as well as dose. THC concentrations typically peak during the act of smoking, while
peak 11-OH THC concentrations occur approximately 9-23 minutes after the start of
smoking. Concentrations of both analytes decline rapidly and are often < 5 ng/mL at 3
hours. Significant THC concentrations (7 to 18 ng/mL) are noted following even a single
puff or hit of a marijuana cigarette. Peak plasma THC concentrations ranged from 46-188
ng/mL in 6 subjects after they smoked 8.8 mg THC over 10 minutes. Chronic users can
have mean plasma levels of THC-COOH of 45 ng/mL, 12 hours after use; corresponding
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THC levels are, however, less than 1 ng/mL. Following oral administration, THC
concentrations peak at 1-3 hours and are lower than after smoking. Dronabinol and THC-
COOH are present in equal concentrations in plasma and concentrations peak at
approximately 2-4 hours after dosing.
It is inadvisable to try and predict effects based on blood THC concentrations
alone, and currently impossible to predict specific effects based on THC-COOH
concentrations. It is possible for a person to be affected by marijuana use with
concentrations of THC in their blood below the limit of detection of the method.
Mathematical models have been developed to estimate the time of marijuana exposure
within a 95% confidence interval. Knowing the elapsed time from marijuana exposure
can then be used to predict impairment in concurrent cognitive and psychomotor effects
based on data in the published literature.
Interpretation of Urine Test Results: Detection of total THC metabolites in urine,
primarily THC-COOH-glucuronide, only indicates prior THC exposure. Detection time
is well past the window of intoxication and impairment. Published excretion data from
controlled clinical studies may provide a reference for evaluating urine cannabinoid
concentrations; however, these data are generally reflective of occasional marijuana use
rather than heavy, chronic marijuana exposure. It can take as long as 4 hours for THC-
COOH to appear in the urine at concentrations sufficient to trigger an immunoassay (at
50ng/mL) following smoking. Positive test results generally indicate use within 1-3 days;
however, the detection window could be significantly longer following heavy, chronic,
use. Following single doses of Marinol®, low levels of dronabinol metabolites have been
detected for more than 5 weeks in urine. Low concentrations of THC have also been
measured in over-the-counter hemp oil products – consumption of these products may
produce positive urine cannabinoid test results.
Effects: Pharmacological effects of marijuana vary with dose, route of administration,
experience of user, vulnerability to psychoactive effects, and setting of use.
Psychological: At recreational doses, effects include relaxation, euphoria, relaxed
inhibitions, sense of well-being, disorientation, altered time and space perception, lack of
concentration, impaired learning and memory, alterations in thought formation and
expression, drowsiness, sedation, mood changes such as panic reactions and paranoia,
and a more vivid sense of taste, sight, smell, and hearing. Stronger doses intensify
reactions and may cause fluctuating emotions, flights of fragmentary thoughts with
disturbed associations, a dulling of attention despite an illusion of heightened insight,
image distortion, and psychosis.
Physiological: The most frequent effects include increased heart rate, reddening of the
eyes, dry mouth and throat, increased appetite, and vasodilatation.
Side Effect Profile: Fatigue, paranoia, possible psychosis, memory problems,
depersonalization, mood alterations, urinary retention, constipation, decreased motor
coordination, lethargy, slurred speech, and dizziness. Impaired health including lung
damage, behavioral changes, and reproductive, cardiovascular and immunological effects
have been associated with regular marijuana use. Regular and chronic marijuana smokers
may have many of the same respiratory problems that tobacco smokers have (daily cough
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and phlegm, symptoms of chronic bronchitis), as the amount of tar inhaled and the level
of carbon monoxide absorbed by marijuana smokers is 3 to 5 times greater than among
tobacco smokers. Smoking marijuana while shooting up cocaine has the potential to
cause severe increases in heart rate and blood pressure.
Duration of Effects: Effects from smoking cannabis products are felt within minutes
and reach their peak in 10-30 minutes. Typical marijuana smokers experience a high that
lasts approximately 2 hours. Most behavioral and physiological effects return to baseline
levels within 3-5 hours after drug use, although some investigators have demonstrated
residual effects in specific behaviors up to 24 hours, such as complex divided attention
tasks. Psychomotor impairment can persist after the perceived high has dissipated. In
long term users, even after periods of abstinence, selective attention (ability to filter out
irrelevant information) has been shown to be adversely affected with increasing duration
of use, and speed of information processing has been shown to be impaired with
increasing frequency of use. Dronabinol has an onset of 30-60 minutes, peak effects
occur at 2-4 hours, and it can stimulate the appetite for up to 24 hours.
Tolerance, Dependence and Withdrawal Effect: Tolerance may develop to some
pharmacological effects of dronabinol. Tolerance to many of the effects of marijuana
may develop rapidly after only a few doses, but also disappears rapidly. Marijuana is
addicting as it causes compulsive drug craving, seeking, and use, even in the face of
negative health and social consequences. Additionally, animal studies suggests marijuana
causes physical dependence. A withdrawal syndrome is commonly seen in chronic
marijuana users following abrupt discontinuation. Symptoms include restlessness,
irritability, mild agitation, hyperactivity, insomnia, nausea, cramping, decreased appetite,
sweating, and increased dreaming.
Drug Interactions: Cocaine and amphetamines may lead to increased hypertension,
tachycardia and possible cardiotoxicity. Benzodiazepines, barbiturates, ethanol, opioids,
antihistamines, muscle relaxants and other CNS depressants increase drowsiness and
CNS depression. When taken concurrently with alcohol, marijuana is more likely to be a
traffic safety risk factor than when consumed alone.
Performance Effects: The short term effects of marijuana use include problems with
memory and learning, distorted perception, difficultly in thinking and problem-solving,
and loss of coordination. Heavy users may have increased difficulty sustaining attention,
shifting attention to meet the demands of changes in the environment, and in registering,
processing and using information. In general, laboratory performance studies indicate that
sensory functions are not highly impaired, but perceptual functions are significantly
affected. The ability to concentrate and maintain attention are decreased during marijuana
use, and impairment of hand-eye coordination is dose-related over a wide range of
dosages. Impairment in retention time and tracking, subjective sleepiness, distortion of
time and distance, vigilance, and loss of coordination in divided attention tasks have been
reported. Note however, that subjects can often “pull themselves together” to concentrate
on simple tasks for brief periods of time. Significant performance impairments are
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usually observed for at least 1-2 hours following marijuana use, and residual effects have
been reported up to 24 hours.
Effects on Driving: The drug manufacturer suggests that patients receiving treatment
with Marinol® should be specifically warned not to drive until it is established that they
are able to tolerate the drug and perform such tasks safely. Epidemiology data from road
traffic arrests and fatalities indicate that after alcohol, marijuana is the most frequently
detected psychoactive substance among driving populations. Marijuana has been shown
to impair performance on driving simulator tasks and on open and closed driving courses
for up to approximately 3 hours. Decreased car handling performance, increased reaction
times, impaired time and distance estimation, inability to maintain headway, lateral
travel, subjective sleepiness, motor incoordination, and impaired sustained vigilance have
all been reported. Some drivers may actually be able to improve performance for brief
periods by overcompensating for self-perceived impairment. The greater the demands
placed on the driver, however, the more critical the likely impairment. Marijuana may
particularly impair monotonous and prolonged driving. Decision times to evaluate
situations and determine appropriate responses increase. Mixing alcohol and marijuana
may dramatically produce effects greater than either drug on its own.
DEC Category: Cannabis
DEC Profile: Horizontal gaze nystagmus not present; vertical gaze nystagmus not
present; lack of convergence present; pupil size normal to dilated; reaction to light
normal to slow; pulse rate elevated; blood pressure elevated; body temperature normal to
elevated. Other characteristic indicators may include odor of marijuana in car or on
subject’s breath, marijuana debris in mouth, green coating of tongue, bloodshot eyes,
body and eyelid tremors, relaxed inhibitions, incomplete thought process, and poor
performance on field sobriety tests.
Panel’s Assessment of Driving Risks: Low doses of THC moderately impair cognitive
and psychomotor tasks associated with driving, while severe driving impairment is
observed with high doses, chronic use and in combination with low doses of alcohol The
more difficult and unpredictable the task, the more likely marijuana will impair
performance.
References and Recommended Reading:
Aceto MD, Scates SM, Lowe JA, Martin BR. Cannabinoid precipitated withdrawal by the
selective cannabinoid receptor antagonist, SR 141716A. Eur J Pharmacol 1995;282(1-
3): R1-2.
Adams IB, Martin BR. Cannabis: pharmacology and toxicology in animals and humans.
Addiction 1996;91(11):1585-614.
Barnett G, Chiang CW, Perez-Reyes M, Owens SM. Kinetic study of smoking marijuana.
J Pharmacokinet Biopharm 1982;10(5):495-506.
Baselt RC. Drug effects on psychomotor performance. Biomedical Publications, Foster
City, CA; pp 403-415;2001.
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Hansteen RW, Miller RD, Lonero L, Reid LD, Jones B. Effects of cannabis and alcohol
on automobile driving and psychomotor tracking. Ann NY Acad Sci 1976;282:240-56.
Heishman SJ. Effects of abused drugs on human performance: Laboratory assessment. In:
Drug Abuse
Handbook. Karch SB, ed. New York, NY: CRC Press, 1998, p219.
Huestis MA. Cannabis (Marijuana) - Effects on Human Performance and Behavior.
Forens Sci Rev 2002;14(1/2):15-60.
Huestis MA, Sampson AH, Holicky BJ, Henningfield JE, Cone EJ. Characterization of
the absorption phase of marijuana smoking. Clin Pharmacol Ther 1992;52(1):31-41.
Huestis MA, Henningfield JE, Cone EJ. Blood cannabinoids: I. Absorption of THC and
formation of 11-OH-THC and THC-COOH during and after marijuana smoking. J
Anal Toxicol 1992;16(5):276-82.
Huestis MA, Henningfield JE, Cone EJ. Blood cannabinoids II: Models for the
prediction of time of marijuana exposure from plasma concentrations of ∆-9-
tetrahydrocannabinol (THC) and 11-nor-9-carboxy-∆-9-tetrahydrocannabinol (THC-
COOH). J Anal Toxicol 1992;16(5):283-90.
Hunt CA, Jones RT. Tolerance and disposition of tetrahydrocannabinol in man. J
Pharmacol Exp Ther 1980;215(1):35-44.
Klonoff H. Marijuana and driving in real-life situations. Science 1974;186(4161);317-
24.
Leirer VO, Yesavage JA, Morrow DG. Marijuana carry-over effects on aircraft pilot
performance. Aviat Space Environ Med 1991;62(3):221-7.
Mason AP, McBay AJ. Cannabis: pharmacology and interpretation of effects. J Forensic
Sci 1985;30(3):615-31.
Physicians’ Desk Reference, Medical Economics Company, Montvale, NJ, 2002.
Plasse TF, Gorter RW, Krasnow SH, Lane M, Shepard KV, Wadleigh RG. Recent
clinical experience with Dronabinol. Pharmacol Biochem Behav 1991;40(3):695-700.
Pope HG Jr, Yurgelun-Todd D. The residual cognitive effects of heavy marijuana use in
college students. JAMA 1996;275(7):521-7.
Ramaekers JG, Robbe HW, O’Hanlon JF. Marijuana, alcohol and actual driving
performance. Hum Psychopharmacol 2000;15(7):551-8.
Robbe HW, O'Hanlon JF. Marijuana and actual driving performance. US Department of
Transportation/National Highway Traffic Safety Administration November: 1-133
(1993). DOT HS 808 078.
Smiley A, Moskowitz HM, Ziedman K. Effects of drugs on driving: Driving simulator
tests of secobarbital, diazepam, marijuana, and alcohol. In Clinical and Behavioral
Pharmacology Research Report. J.M. Walsh, Ed. U.S. Department of Health and
Human Services, Rockville, 1985, pp 1-21.
Solowij N, Michie PT, Fox AM. Differential impairment of selective attention due to
frequency and duration of cannabis use. Biol Psychiatry 1995;37(10):731-9.
Thornicroft G. Cannabis and psychosis. Is there epidemiological evidence for an
association Br J Psychiatry 1990;157:25-33.
Varma VK, Malhotra AK, Dang R, Das K, Nehra R. Cannabis and cognitive functions: a
prospective study. Drug Alcohol Depend 1988;21(2):147-52.
WHO Division of Mental Health and Prevention of Substance Abuse: Cannabis: a health
perspective and research agenda. World Health Organization 1997.
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Carisoprodol (and Meprobamate)
Carisoprodol is a white, crystalline powder. Meprobamate is a white powder. Both are
available in tablet form.
Synonyms: Carisoprodol: N-isopropyl-2-methyl-2-propyl-1,3-propanediol dicarbamate;
Soma®, Sodol®, Soprodol®, Soridol®. Meprobamate: Miltown®, Equanil®,
Equagesic®, Meprospan®.
Source: Carisoprodol and meprobamate are available by prescription only.
Carisoprodol itself is not a federally scheduled compound, while meprobamate is a
Schedule IV drug. Soma® is available as a 350 mg strength round, white tablet; Soma®
Compound is a 250 mg strength two-layered, white and light orange round tablet (also
contains aspirin); and Soma® Compound with Codeine is a 250 mg strength two-layered,
white and yellow oval tablet (also contains aspirin and codeine phosphate) and is a
schedule III controlled substance. Miltown® is available as a 200 mg and 400 mg
strength white tablet; Equanil® is a 200 mg and 400 mg strength tablet; and Equagesic®
is a 200 mg strength two-layered, pink and yellow, round tablet (also contains aspirin).
Drug Class: Carisoprodol: muscle relaxant, CNS depressant; Meprobamate:
antianxiety, CNS depressant.
Medicinal and Recreational Uses: Carisoprodol is a centrally acting skeletal muscle
relaxant prescribed for the treatment of acute, musculoskeletal pain. Meprobamate is a
major metabolite of carisoprodol, and is a CNS depressant in its own right, indicated for
the management of anxiety disorders or for short-term treatment of anxiety symptoms.
Use of these drugs begins with prescription for muscular pain or anxiety, and abuse
develops for their sedative-hypnotic effects, resulting in increased dosage without
medical advice, or continued use after pain or anxiety has subsided.
Potency, Purity and Dose: Carisoprodol is present as a racemic mixture. During
treatment, the recommended dose of carisoprodol is for one 350 mg tablet taken three
times daily and at bedtime (1400 mg/day). The usual dose for meprobamate is one
400 mg taken four times daily, or daily divided doses of up to 2400 mg. To control
chronic pain, carisoprodol is often taken concurrently with other drugs, particularly
opiates, benzodiazepines, barbiturates, and other muscle relaxants.
Route of Administration: Oral.
Pharmacodynamics: The pharmacological effects of carisoprodol appear to be due to
the combination of the effects of carisoprodol and its active metabolite, meprobamate.
Meprobamate is equipotent to carisoprodol. There is some evidence suggesting
carisoprodol is a GABA A receptor indirect agonist with CNS chloride ion channel
conductance effects. In animals, carisoprodol produces muscle relaxation by blocking
interneuronal activity and depressing transmission of polysynaptic neurons in the
descending reticular formation and spinal cord. It is unknown if this mechanism of action
is also present in humans. In addition to the desired skeletal muscle relaxing effects,
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carisoprodol and meprobamate produce weak anticholinergic, antipyretic and analgesic
properties.
Pharmacokinetics: Carisoprodol is rapidly absorbed from the gastrointestinal tract and
rapidly distributed throughout the CNS. Protein binding is approximately 60%.
Carisoprodol is predominantly dealkylated to meprobamate in the liver, and to a lesser
extent hydroxylated to hydroxycarisoprodol and hydroxymeprobamate, followed by
conjugation and excretion. The half-life of carisoprodol is approximately 100 minutes.
Some individuals have impaired metabolism of carisoprodol, and exhibit a half life of 2-3
times that in normal subjects. The half-life of meprobamate is many times longer,
between 6 and 17 hours. As a result of the significantly longer half-life of meprobamate
relative to carisoprodol, accumulation of meprobamate during chronic therapy may occur.
Molecular Interactions / Receptor Chemistry: The cytochrome P450 2C19 isoenzyme
is responsible for the conversion of carisoprodol to meprobamate. Potential inhibitors of
the 2C19 isoenzyme could decrease the rate of drug elimination if administered
concurrently, while potential inducers of the 2C19 isoenzyme could increase the rate of
elimination.
Blood to Plasma Concentration Ratio: Data not available for carisoprodol; 3.3 to 5.0
for meprobamate.
Interpretation of Blood Concentrations: Following therapeutic doses of carisoprodol,
blood concentrations are typically between 1 and 5 mg/L for carisoprodol, and between 2
and 6 mg/L for meprobamate. A single oral dose of 350 mg carisoprodol produced
average peak plasma concentrations of 2.1 mg/L carisoprodol at one hour, declining to
0.24 mg/L at 6 hours. Following a single oral dose of 700 mg, average peak plasma
concentrations of carisoprodol were 3.5 mg/L at 45 minutes, and meprobamate
concentrations of 4.0 mg/L were obtained in 220 minutes. A single oral dose of 700 mg
carisoprodol has also produced peak plasma concentrations of 4.8 mg/L carisoprodol.
Following administration of meprobamate in the treatment of anxiety, concentrations are
typically around 10 mg/L, but can range between 3 and 26 mg/L. A single oral dose of
1200 mg meprobamate produced concentrations of 15.6 mg/L at 4 hours. Plasma
meprobamate concentrations of greater than 100 mg/L have been associated with deep
coma; light coma between 60 and 120 mg/L; and patients with levels below 50 mg/L are
invariably conscious.
Interpretation of Urine Test Results: Both drugs are excreted into the urine and are
likely be detectable for several days following cessation of use. Less than 1% of a single
oral dose of carisoprodol is excreted unchanged in the 24 hour urine, with meprobamate
accounting for 4.7% of the dose. Following administration of meprobamate, up to 11% of
a single dose is excreted in the urine in 24 hours.
Effects:
Psychological: Dizziness, drowsiness, sedation, confusion, disorientation, slowed
thinking, lack of comprehension, drunken behavior, obtunded, coma.
- 14 -

Physiological: CNS depression, nystagmus (becoming more evident as concentrations
increase), loss of balance and coordination, sluggish movements, slurred speech,
bloodshot eyes, ataxia, tremor, sleep disturbances.
Side Effect Profile: Agitation, tremor, paresthesia, irritability, depression, facial
flushing, headache, vertigo, postural hypotension, fainting, weakness, loss of balance and
coordination, impairment of visual accommodation, tachycardia, nausea, vomiting, and
stomach upset. In abuse or overdose, subjects are consistently sedated and obtunded,
frequently becoming comatose. Overdose symptoms may include shallow breathing,
clammy skin, dilated pupils, weak and rapid pulse, paradoxical excitement and insomnia,
convulsions, and possible death. Meprobamate overdose can produce drowsiness, ataxia,
severe respiratory depression, severe hypotension, shock, heart failure, and death.
Duration of Effects: The effects of carisoprodol begin within 30 minutes of oral
administration, and last for up to 4-6 hours. In overdose, coma may last from several
hours to a day or more. Meprobamate has a much longer duration of effect than
carisoprodol due to a much longer half-life.
Tolerance, Dependence and Withdrawal: Development of abuse and moderate physical
and psychological dependence can occur with chronic use of both carisoprodol and
meprobamate. Abrupt discontinuation of long-term use can be followed by mild
withdrawal symptoms such as anxiety, abdominal cramps, insomnia, headache, nausea,
vomiting, ataxia, tremor, muscle twitching, confusion, and occasionally chills,
convulsions and hallucinations. Onset of withdrawal from meprobamate occurs within
12-48 hours following cessation of use, and can last a further 12-48 hours. Carisoprodol
has been shown to produce cross-tolerance to barbiturates.
Drug Interactions: Alcohol enhances the impairment of physical abilities produced by
carisoprodol, and increased sedation, extreme weakness, dizziness, agitation, euphoria
and confusion may be observed. Alcohol also inhibits the metabolism of meprobamate
and produces an additive depressant effect on the CNS that includes sleepiness,
disorientation, incoherence and confusion. The concurrent administration of other
centrally acting drugs such as opiates, benzodiazepines, barbiturates, and other muscle
relaxants can contribute to impairment. Meprobamate may enhance the analgesic effects
of other drugs.
Performance Effects: Very limited studies are available for carisoprodol, however,
single oral doses of 700 mg have not been shown to affect psychomotor and cognitive
tests within 3 hours of dosing, to a significant degree. In contrast, single doses of
meprobamate are capable of causing significant performance impairment. Performance
effects include impaired divided attention, impaired coordination and balance, slowed
reflexes and increased reaction time. With chronic dosing of either drug, it is likely that
decrements in psychomotor performance would be even more pronounced.
Effects on Driving: The drug manufacturer suggests patients should be warned that
carisoprodol and meprobamate may impair the mental and/or physical abilities required
- 15 -

for the performance of potentially hazardous tasks, such as driving a motor vehicle.
Reported signs of psychomotor and cognitive impairment in subjects found to be driving
under the influence of carisoprodol/meprobamate include poor perception, impaired
reaction time, slow driving, confusion, disorientation, inattentiveness, slurred or thick
speech, slow responses, somnolence, lack of balance and coordination, unsteadiness, and
difficulty standing, walking or exiting vehicles.
Logan et al., 2000 describes 21 driving under the influence cases where
carisoprodol and/or meprobamate were the only drugs detected. The mean carisoprodol
and meprobamate concentrations were 4.6 mg/L (range 0-15 mg/L) and 14.5 mg/L (range
1-36 mg/L), respectively. Signs of impairment were noted at blood concentrations as low
as 1 mg/L of meprobamate, however, the most severe driving impairment and the most
overt symptoms of intoxication occurred in drivers whose combined carisoprodol and
meprobamate blood concentrations were greater than 10 mg/L. Signs consistent with
CNS depression were typically observed, including poor balance and coordination,
horizontal gaze nystagmus, slurred speech, dazed or groggy appearance, depressed
reflexes, slow movements, disorientation to place and time, and a tendency to dose off or
fall asleep. Many subjects were involved in accidents, and other observed driving
behaviors included extreme lane travel and weaving, striking other vehicles and fixed
objects, slow speed, and hit and run accidents where the subject appeared unaware they
had hit another vehicle.
DEC Category: CNS depressant
DEC Profile: Horizontal gaze nystagmus present; vertical gaze nystagmus may be
present in high doses; lack of convergence present; pupil size normal to dilated; reaction
to light slow; pulse rate normal to down; blood pressure normal to down; body
temperature normal to down. Other characteristic indicators may include slurred speech,
drowsiness, disorientation, drunken behavior without the odor of alcohol, and poor
performance on field sobriety tests.
Panel’s Assessment of Driving Risks: A single therapeutic dose of carisoprodol is
unlikely to cause significant performance impairment. However, single therapeutic doses
of meprobamate and chronic doses of carisoprodol may produce moderate to severe
impairment of psychomotor skills associated with safe driving.
References and Recommended Reading:
Bailey DN, Shaw RF. Interpretation of blood glutethimide, meprobamate, and
methyprylon concentrations in non-fatal and fatal intoxications. J Tox Clin Tox
1983;20:133-45.
Baselt RC. Drug effects on psychomotor performance. Biomedical Publications, Foster
City, CA; pp 74-5, pp 238-40;2001.
Finkle BS. The identification, quantitative determination, and distribution of
meprobamate and glutethimide in biological material. J Forensic Sci 1967;12(4):509-
28.
Logan BK, Case GA, Gordon AM. Carisoprodol, meprobamate, and driving impairment.
J Forens Sci 2000;45(3):619-23.
- 16 -

Maddock RK, Bloomer HA. Meprobamate overdosage: evaluation of its severity and
methods of treatment. JAMA 1967;201:123-7.
Marinetti-Scheff L, Ludwig RA. Occurrence of carisoprodol in casework associated with
driving under the influence violations by the forensic toxicology subunit of the
Michigan state police crime laboratory. Presented at the annual meeting of the
American Academy of Forensic Sciences, New York, NY, 1997.
Physicians’ Desk Reference, Medical Economics Company, Montvale, NJ, 2002.
Reeves RR, Pinkofsky HB, Carter OS. Carisoprodol: A drug of continuing abuse. JAMA
1997;97(12):723-4.
Rust GS, Hatch R, Gums JG. Carisoprodol as a drug of abuse. Arch Fam Med
1993;2:429-32.
Weatherman R, Crabb DW. Alcohol and medication interactions. Alc Res & Health
1999;23(1):40-53.
- 17 -

- 18 -

Cocaine
Cocaine hydrochloride is a white to light brown crystalline powder, shiny rather than dull
in appearance. Cocaine base is white to beige in color; waxy/soapy to flaky solid chunks.
Synonyms: Methylbenzoylecgonine. Cocaine hydrochloride: coke, snow, flake, blow,
cane, dust, shake, toot, nose candy, white lady. Cocaine base: crack, rock, free-base.
Source: Naturally derived CNS stimulant extracted and refined from the leaves of the
coca plant (Erythroxylon coca), grown primarily in the Andean region of South America
and to a lesser extent in India, Africa and Indonesia. The picked coca leaves are dried in
the open air and then “stomped” as part of the process to extract the alkaloid, resulting in
coca paste and eventually cocaine hydrochloride. It is illegal to possess and sell cocaine
in the U.S. and cocaine is a Schedule II controlled substance. “Crack” is the street name
given to cocaine that has been processed from cocaine hydrochloride. It is prepared by
adding baking soda to aqueous cocaine hydrochloride and heating it until the free-base
cocaine precipitates into small pellets. The mixture is cooled and filtered, and then the
“rocks” are smoked in a crack pipe.
Drug Class: CNS stimulant, local anesthetic.
Medical and Recreational Uses: Minor use as a topical local anesthetic for ear, nose
and throat surgery. Traditionally, the coca leaves are chewed or brewed into a tea for
refreshment and to relieve fatigue. Recreationally, cocaine is used to increase alertness,
relieve fatigue, feel stronger and more decisive, and is abused for its intense euphoric
effects.
Potency, Purity and Dose: In ear, nose and throat surgery cocaine is commercially
supplied as the hydrochloride salt in a 40 or 100 mg/mL solution. Depending on the
demographic region, street purity of cocaine hydrochloride can range from 20-95%,
while that of crack cocaine is 20-80%. The hydrochloride powder is often diluted with a
variety of substances such as sugars for bulk (lactose, sucrose, inositol, mannitol), other
CNS stimulants (caffeine, ephedrine, phenylpropanolamine), or other local anesthetics
(lidocaine, procaine, benzocaine). Commonly abused doses are 10-120 mg. Repeated
doses are frequently taken to avoid the dysphoric crash that often follows the initial
intense euphoric effects. Cocaine is frequently used in combination with other drugs;
injected with heroin (“speedball”) or taken with alcohol to reduce irritability; smoked
with phencyclidine (“tick”); and smoked in marijuana blunts (“turbo”).
Route of Administration: Topically applied for use as a local anesthetic. Recreationally,
coca leaves can be chewed, however, cocaine abusers typically smoke “crack” in a glass
pipe or inject the hydrochloride salt intravenously. Cocaine hydrochloride can be
smoked to some effect but this is very inefficient as the powder tends to burn rather than
vaporize. Snorting (insufflation/intranasal) is also popular. Subcutaneous injection (skinpopping)
is rarely used.
- 19 -

Pharmacodynamics: Cocaine is a strong CNS stimulant that interferes with the
reabsorption process of catecholamines, particularly dopamine, a chemical messenger
associated with pleasure and movement. Cocaine prevents the reuptake of dopamine by
blocking the dopamine transporter which leads to increased extracellular dopamine,
resulting in chronic stimulation of postsynaptic dopamine receptors. This results in the
euphoric ‘rush’. When dopamine levels subsequently fall, users experience a dysphoric
‘crash’. Similarly, cocaine interferes with the uptake of norepinephrine and serotonin (5-
HT), leading to accumulation of these neurotransmitters at postsynaptic receptors. As a
local anesthetic, cocaine reversibly blocks the initiation and conduction of the nerve
impulse. Cocaine additionally produces vasoconstriction and dilated pupils.
Pharmacokinetics: Cocaine is rapidly absorbed following smoking, snorting and
intravenous administration. Bioavailability is 57% following snorting and ~70%
following smoking. Cocaine is 91% bound in plasma. Cocaine is extensively metabolized
to a variety of compounds: benzoylecgonine, ecgonine, and ecgonine methyl ester are the
major metabolites and are centrally inactive. Benzoylecgonine is produced upon loss of
the methyl group and is the major urinary metabolite. Norcocaine is a very minor
metabolite, but is active and neurotoxic. Cocaethylene, formed following concurrent
ingestion of cocaine and alcohol, is also active and is equipotent to cocaine in blocking
dopamine reuptake. The apparent half-life for cocaine is short, approximately
0.8 ± 0.2 hours, while the half-life of benzoylecgonine is 6 hours.
Molecular Interactions / Receptor Chemistry: The cytochrome P450 3A4 isoenzyme is
responsible for the N-demethylation of cocaine to norcocaine. Potential inhibitors of the
3A4 isoenzyme could decrease the rate of drug elimination if administered concurrently,
while potential inducers could increase the rate of drug elimination. Cocaine itself is an
inhibitor of the CYP2D6 isoform.
Blood to Plasma Concentration Ratio: averages ~ 1.0
Interpretation of Blood Concentrations: The presence of cocaine at a given blood
concentration cannot usually be associated with a degree of impairment or a specific
effect for a given individual without additional information. This is due to many factors,
including individual levels of tolerance to the drug and artifactual changes in cocaine
concentrations on storage. There is a large overlap between therapeutic, toxic and lethal
cocaine concentrations and adverse reactions have been reported after prolonged use even
with no measurable parent drug in the blood. Typical concentrations in abuse range from
0-1mg/L, however, concentrations up to 5mg/L and higher are survivable in tolerant
individuals. After single doses of cocaine, plasma concentration typically average 0.2-0.4
mg/L. Repeated doses of cocaine may result in concentrations greater than 0.75 mg/L.
Following intranasal administration of 106 mg, peak plasma concentrations of
cocaine averaged 0.22 mg/L at 30 minutes, while benzoylecgonine concentrations
averaged 0.61 mg/L at 3 hours. Oral administration of 140 mg/70 kg cocaine resulted in
peak plasma concentrations averaging 0.21 mg/L of cocaine at 1 hour. Single 32 mg
intravenous doses of cocaine produced an average peak plasma concentration of 0.31
mg/L of cocaine within 5 minutes. Smoking 50 mg of cocaine base resulted in peak
- 20 -

plasma cocaine concentrations averaging 0.23 mg/L at ~ 45 minutes and 0.15 mg/L of
benzoylecgonine at 1.5 hours.
Interpretation of Urine Test Results: Urinary excretion is less than 2% for unchanged
cocaine, 26-39% for benzoylecgonine, and 18-22% for ecgonine methyl ester. 64-69% of
the initial dose is recovered after 3 days. Very low concentrations of cocaine may be
detected in urine during the initial few hours, however, benzoylecgonine persists in urine
at detectable concentrations from 2-4 days. Chronic, heavy use of cocaine can result in
detectable amounts of benzoylecgonine in urine for up to 10 days following a binge.
Effects:
Early phase – Psychological: Euphoria, excitation, feelings of well-being, general
arousal, increased sexual excitement, dizziness, self-absorbed, increased focus and
alertness, mental clarity, increased talkativeness, motor restlessness, offsets fatigue,
improved performance in some simple tasks, and loss of appetite. Higher doses may
exhibit a pattern of psychosis with confused and disoriented behavior, delusions,
hallucinations, irritability, fear, paranoia, antisocial behavior, and aggressiveness.
Physiological: Increased heart rate and blood pressure, increased body temperature,
dilated pupils, increased light sensitivity, constriction of peripheral blood vessels, rapid
speech, dyskinesia, nausea, and vomiting.
Late phase - Psychological: Dysphoria, depression, agitation, nervousness, drug craving,
general CNS depression, fatigue, insomnia. Physiological: Itching/picking/scratching,
normal heart rate, normal pupils.
Side Effect Profile: Nervousness, restlessness, tremors, anxiety, and irritability. Chronic
use may lead to personality changes, hyperactivity, psychosis, paranoia, and fear.
Cocaine overdose can be characterized by agitation, enhanced reflexes, hostility,
headache, tachycardia, irregular respiration, chills, nausea, vomiting, abdominal pain, rise
in body temperature, hallucinations, convulsions, delirium, unconsciousness, seizures,
stroke, cerebral hemorrhage, heart failure, and death from respiratory failure. Cocaine
excited delirium is a syndrome often caused by excessive cocaine use, and is associated
with a dissociative state, violence to persons and property, exaggerated strength,
hyperthermia, cardiorespiratory arrest and sudden death.
Burnt lips and fingers from crack pipes are frequently seen, as are rashes and skin
reddening from scratching. Smokers may suffer from acute respiratory problems
including cough, shortness of breath, and severe chest pains with lung trauma and
bleeding. Prolonged cocaine snorting can result in ulceration of the mucous membrane of
the nose. The injecting drug user is at risk for transmitting or acquiring HIV
infection/AIDS if needles or other injection equipment are shared.
Duration of Effects: The faster the absorption the more intense and rapid the high, but
the shorter the duration of action. Injecting cocaine produces an effect within 15-30
seconds. A hit of smoked crack produces an almost immediate intense experience and
will typically produce effects lasting 5-15 minutes. Similarly, snorting cocaine produces
effects almost immediately and the resulting high may last 15-30 minutes. The effects
- 21 -

onset more slowly after oral ingestion (~1 hour). General effects will persist for 1-2 hours
depending on the dose and late phase effects following binge use may last several days.
Tolerance, Dependence and Withdrawal Effects: Cocaine is a powerfully addictive
drug of abuse and an appreciable initial tolerance to the euphoric high may develop.
Cocaine is psychologically addicting, particularly with heavy or frequent use, and
possibly physically addicting as well. The short duration of effects is one reason leading
to probability of addition. As effects wear off, more drug is frequently administered and a
pattern of repeated use occurs. Following binge use of cocaine, the “crash” can last from
9 hours to 4 days and may consist of agitation, depressed moods, insomnia to
hypersomnolence, and initial drug craving. Withdrawal symptoms can typically last from
1-3 weeks and may consist of alternating low and high drug craving, low to high anxiety,
paranoia, dysphoria, depression, apathy, irritability, disorientation, hunger, fatigue,
bradycardia, and long periods of sleep.
Drug Interactions: The combined use of cocaine and ethanol forms cocaethylene in the
body, a substance which intensifies cocaine’s euphoric effects while possibly increasing
the risk of sudden death. In laboratory studies, cocaine has been shown to partially
reverse some of the adverse effects of alcohol, but may contribute to the detrimental
effects of marijuana.
Performance Effects: Most laboratory-based studies have been limited by the low doses
of cocaine that were allowed. At these single low doses, studies have shown performance
enhancement in attentional abilities and increased behavioral and cortical arousal, but
have no enhancement of effects on learning, memory, and other cognitive processes.
Faster reaction times and diminished effects of fatigue have been observed.
Improvements were greatest in behaviorally impaired subjects (e.g. sleep deprived,
fatigued, or concurrent use of ethanol) and least improvements were observed in wellrested,
healthy subjects. More deleterious effects are expected after higher doses, chronic
ingestion and during drug withdrawal, and include agitation, anxiety, distress, inability to
focus on divided attention tasks, inability to follow directions, confusion, hostility, time
distortion, and poor balance and coordination. Laboratory studies have also demonstrated
increased risk taking (rapid braking or steering) and deleterious effects on vision related
to mydriasis. Self-reported increases in sensitivity to light, seeing halos around bright
objects, flashes or movement of light in peripheral field, difficulty focusing, blurred
vision, and glare recovery problems have been reported.
Effects on Driving: Observed signs of impairment in driving performance have
included subjects speeding, losing control of their vehicle, causing collisions, turning in
front of other vehicles, high-risk behavior, inattentive driving, and poor impulse control.
As the effects of cocaine wear off subjects may suffer from fatigue, depression,
sleepiness, and inattention. In epidemiology studies of driving under the influence cases,
accidents, and fatally injured drivers, between 8-23% of subjects have had cocaine and/or
metabolites detected in their blood. An examination of 253 fatally injured drivers in
Wayne County, Michigan between 1996-1998, found that 10% of cases were positive for
blood cocaine and/or metabolites. On review of accident and witness reports, aggressive
- 22 -

driving (high speed and loss of vehicle control) was revealed as the most common
finding. Ethanol was detected in 56% of these cases, and all of these drivers lost control
of their vehicles. In Memphis, Tennessee in 1993, 13% of 150 drivers stopped for
reckless driving were determined to be driving under the influence of cocaine based on
observations of behavior and appearance, performance on field sobriety tests, and
positive urine cocaine tests.
A 25 year-old male driver, who made an improper turn against oncoming traffic,
had a blood cocaine concentration of 0.04 mg/L and 0.06 mg/L of benzoylecgonine, 2
hours after the collision. A 30 year-old female caused an accident after failing to stop at a
traffic light; the driver admitted to ingesting a large amount of cocaine ~ 2.5 hours prior
to the collision, and 0.32 mg/L cocaine was detected in her blood 1 hour post accident.
DEC Category: CNS stimulant.
DEC Profile: Horizontal gaze nystagmus not present; vertical gaze nystagmus not
present; lack of convergence not present; pupil size dilated; reaction to light slow; pulse
rate elevated; blood pressure elevated; body temperature elevated. Other characteristic
indicators may include excessive activity, increased alertness, talkativeness, irritability,
argumentativeness, nervousness, body tremors, anxiety, redness to nasal area and runny
nose.
Panel’s Assessment of Driving Risks: Single low doses of cocaine may improve mental
and motor performance in persons who are fatigued or sleep deprived, however, cocaine
does not necessarily enhance the performance of otherwise normal individuals. Cocaine
may enhance performance of simple tasks but not complex, divided-attention tasks such
as driving. Most laboratory studies have been limited by the low single doses of cocaine
administered to subjects. At these low doses, most studies showed performance
enhancement in attentional abilities but no effect on cognitive abilities. Significant
deleterious effects are expected after higher doses, chronic ingestion, and during the crash
or withdrawal phase.
References and Recommended Reading:
Baselt RC. Drug effects on psychomotor performance. Biomedical Publications, Foster
City, CA; pp 115-21;2001.
Brookoff D, Cook CS, Williams C, Mann CS. Testing reckless drivers for cocaine and
marijuana. New Engl J Med 1994;331:518-22.
Community Epidemiology Working Group, National Institute on Drug Abuse.
Epidemiological trends in drug abuse; Proceedings of the Community Epidemiology
Working Group, Vol 1;June 2000.
Ellinwood EH, Nikaido AM. Stimulant induced impairment: A perspective across dose
and duration of use. Alcohol Drugs & Driving 1987;3(1):19-24.
Gawin FH, Kleber HD. Abstinence symptomatology and psychiatric diagnosis in
cocaine abusers. Arch Gen Psych 1986;43:107-13.
- 23 -

Isenschmid DS. Cocaine - Effects on Human Performance and Behavior. Forens Sci Rev
2002;14(1/2):61-100.
Javaid JI, Fischman MW, Schuster H, Dekirmenjian H, Davis JM. Cocaine plasma
concentration: Relation to physiological and subjective effects in humans. Science
1978;202:227-8.
Jeffcoat AR, Perez-Reyes M, Hill JM, Sadler BM, Cook CE. Cocaine disposition in
humans after intravenous injection, nasal insufflation (snorting), or smoking. Drug
Metab Dispos 1989;17:153-9.
Marzuk PM, Tardiff K, Leon AC, Stajic M, Morgan EB, Mann JJ. Prevalence of recent
cocaine use among motor vehicle fatalities in New York City. J Am Med Assoc
1990;263:250-6.
Physicians’ Desk Reference, Medical Economics Company, Montvale, NJ, 2002
Satel SL, Price LH, Palumbo J, McDougle CJ, Krystal JH, Gawin F, Charney DS,
Heninger GR, Kleber HD. Clinical phenomenology and neurobiology of cocaine
abstinence: A prospective inpatient study. Am J Psychiatry 1991;148(12):1712-6.
Siegel R. Cocaine use and driving behavior. Alcohol Drugs and Driving 1987;3(1):1-7.
Stillman R, Jones RT, Moore D, Walker J, Welm S. Improved performance 4 hours after
cocaine. Psychopharmacol 1993;110:415-20.
Van Dyke C, Ungerer J, Jatlow P, Barash PG, Byck R. Oral cocaine plasma
concentrations and central effects. Science 1978;200:211-3.
Weddington WW, Brown BS, Haertzen CA, Cone EJ, Dax EM, Herning RI, Michaelson
BS. Changes in mood, craving, and sleep during short-term abstinence reported by
male cocaine addicts. Arch Gen Psych 1990;47:861-7.
- 24 -

Dextromethorphan
Dextromethorphan is a white powder. Available primarily in tablet, capsule and liquid
form.
Synonyms: 3-methoxy-17-methyl-9α, 13α, 14 α-morphinan hydrobromide
monohydrate; dextromethorphan hydrobromide, DXM, “robbo tripping”; Anaplex-DM®,
Diabe-Tuss DM, Benylin®, Pertussin®, Delsym®, Sucrets®, Bromfed-DM®,
Robitussin®, Vicks Formula 44, etc.
Source: Synthetic analog of codeine and d-isomer of 3-methoxy-N-methymorphinan.
Available as lozenges, capsules, tablets, and cough syrups, in a variety of prescription
medications and over-the-counter cough and cold remedies. Products contain
dextromethorphan alone or in combination with guaifenesin, brompheniramine,
pseudoephedrine, phenylephrine, promethazine, codeine, acetaminophen, and/or
chlorpheniramine. For example, Diabe-Tuss DM syrup contains 15 mg
dextromethorphan; Benylin® Adult and Pediatric contain 15 mg and 7.5 mg
dextromethorphan, respectively; and Anaplex-DM® contains 30 mg dextromethorphan, 4
mg brompheniramine and 60 mg pseudoephedrine.
Drug Class: Non-opioid antitussive, cough suppressant, CNS depressant (in high
doses).
Medical and Recreational Uses: Used as an antitussive for temporary relief of coughs
caused by minor throat and bronchial irritation. Recreationally used for effects ranging
from mild stimulation and intoxication, to dissociation.
Potency, Purity and Dose: As an antitussive, the recommended dosage for adults and
children aged 12 years and older is 60-120 mg daily in divided doses; for children aged 6-
12 years, 30-60 mg daily in divided doses; and for children aged 2-6 years, 15-30 mg
daily in divided doses. Each brand contains different quantities of dextromethorphan,
generally 20-30 mg per dose, and the majority contain other drugs as previously
mentioned. Approximate recreational doses are: threshold dose 80-90 mg; light 100-200
mg; common 200-400 mg; strong 400-600; and heavy dose 600-1500 mg.
Route of Administration: Oral.
Pharmacodynamics: Dextromethorphan acts centrally to elevate the threshold for
coughing, and has no significant analgesic or sedative properties at antitussive doses. It is
proposed that dextromethorphan is a glutamate and NMDA antagonist, and blocks the
dopamine reuptake site. It may also increase 5HT 1A activity possibly via NMDA
antagonism.
Pharmacokinetics: Dextromethorphan is rapidly absorbed from the gastrointestinal tract
and peak plasma concentrations are reached in approximately 2.5 hours.
Dextromethorphan is widely distributed, and is rapidly and extensively metabolized by
the liver. Dextromethorphan is demethylated to dextrorphan, an active metabolite, and to
- 25 -

3-methoxymorphinan and 3-hydroxymorphinan. It is primarily excreted as unchanged
parent drug and dextrorphan.
Molecular Interactions / Receptor Chemistry: The cytochrome P450 2D6 isoenzyme is
responsible for the conversion of dextromethorphan to dextrorphan; and P450 3A4 and
3A5 isoenzymes are responsible for converting dextromethorphan to
3-methoxymorphinan and 3-hydroxymorphinan. Potential inhibitors of these isoenzymes
could decrease the rate of dextromethorphan elimination if administered concurrently,
while potential inducers could increase the rate of elimination.
Blood to Plasma Concentration Ratio: Data not available.
Interpretation of Blood Concentrations: A single 20 mg oral dose of dextromethorphan
produced peak concentrations of 1.8 ng/mL in serum after 2.5 hours. Chronic oral dosing
of 120 mg daily, in divided doses, resulted in peak plasma dextromethorphan
concentrations of 0.5-5.9 ng/mL (mean 2.4 ng/mL) in extensive metabolizers, and 182-
231 ng/mL (mean 207 ng/mL) in poor metabolizers.
Interpretation of Urine Test Results: In a 24 hour period, less than 2.5% of a dose is
excreted unchanged in the urine, while up to 30% of the conjugated dextrorphan is
excreted.
Effects: At recommended doses, dextromethorphan produces little or no CNS
depression. At recreational doses, positive effects may include acute euphoria, elevated
mood, dissociation of mind from body, creative dream-like experiences, and increased
perceptual awareness. Other effects include disorientation, confusion, pupillary dilation,
and altered time perception, visual and auditory hallucinations, and decreased sexual
functioning. Recreational doses of approximately 100-200 mg have a mild, stimulant
effect (likened to MDA); doses of 200-500 mg produce a more intoxicating effect
(likened to being ‘drunk and stoned’); 500-1000 mg may result in mild hallucinations and
a mild dissociate effect (likened to a low dose of ketamine) and an overall disturbance in
thinking, senses and memory; while doses over 1000 mg may produce a fully dissociative
effect (likened to a high dose of ketamine). Recreationally abused doses are capable of
impairing judgment, memory, language, and other mental performances.
Side Effect Profile: Adverse effects with recommended antitussive doses are rare.
However, nausea, other gastrointestinal disturbances, slight drowsiness and dizziness can
occur. Following acute doses of between 250-1500 mg, the following clinical and
overdose symptoms have been reported: excitation, nausea, vomiting, drowsiness,
dizziness, blurred vision, nystagmus, dilated pupils, body itching, rash, ataxia, sweating,
hot/cold flashes, fever, hypertension, shallow respiration, urinary retention, diarrhea,
opisthotonos (spasm where head and heels are bent back, and torso is bent forward), toxic
psychosis (hyperactivity, marked visual and auditory hallucinations), coma, and an
increase in heart rate, blood pressure and body temperature. Side effects can be serious if
very large doses of the combined preparations are ingested; for example, guaifenesin and
- 26 -

dextromethorphan can cause severe nausea and vomiting; chlorpheniramine and
dextromethorphan can cause seizure, loss of consciousness and bleeding.
Duration of Effects: Dextromethorphan exerts its antitussive effects within 15-30
minutes of oral administration. The duration of action is approximately 3-6 hours with
conventional dosage forms.
Tolerance, Dependence and Withdrawal Effects: At recommended antitussive doses,
addiction does not occur. Mild psychological dependence and depression may occur with
regular use of increased doses. Abrupt discontinuation of higher doses may produce
insomnia, dysphoria and depression. Poor metabolizers of dextromethorphan have been
shown to tolerate lower doses of the drug compared to extensive metabolizers, and report
greater sedation, dysphoria and psychomotor impairment. Preliminary evidence also
suggests that extensive metabolizers may report a greater dextromethorphan abuse
potential due to the increased rate of metabolism to the active metabolite dextrorphan.
Drug Interactions: Should not be taken with Monoamine Oxide Inhibitors (MAOIs)
and Selective Serotonin Reuptake Inhibitors (SSRIs) because of an apparent serotonin
syndrome (fever, hypertension, arrhythmias). Should be used with caution in atopic
children due to histamine release. Additive CNS depressant effects when co-administered
with alcohol, antihistamines, psychotropics, and other CNS depressant drugs.
Performance Effects: Minimal at therapeutic levels, however, with high doses one can
expect gross cognitive and psychomotor impairment.
Effects on Driving: Little to no effect at therapeutic levels, however with high doses
one could expect significant impairment. The drug manufacturer states that the combined
preparation of promethazine and dextromethorphan may cause marked drowsiness or
impair the mental and/or physical abilities required for the performance of potentially
hazardous tasks, such as driving a vehicle. Patients should be told to avoid engaging in
such activities until it is known that they do not become drowsy or dizzy. Similar effects
could be seen with other combined dextromethorphan preparations.
DEC Category: CNS depressant
DEC Profile: Data not available; however, the profile for a CNS depressant is:
horizontal gaze nystagmus present; vertical gaze nystagmus present at high doses; lack of
convergence present; pupil size normal to dilated; reaction to light slow; pulse rate down;
blood pressure down; body temperature normal. Such effects are more likely to be seen
following recreational doses of dextromethorphan.
Panel’s Assessment of Driving Risks: Minimal to no risk at therapeutic levels.
Potentially mild to moderate driving risk with higher recreational use.
References and Recommended Reading:
Cranston JW, Yoast R. Abuse of dextromethorphan. Arch Fam Med 1999;8(2):99-100.
- 27 -

de Zeeuw RA, Jonkman JHG. Genetic differences in oxidative drug metabolism. In
Proceedings of the International Association of Forensic Toxicologists, Gronigen,
Netherlands, 1988,pp 53-64.
Pender ES, Parks BR. Toxicity with dextromethorphan containing preparations: A
literature review and report of two additional cases. Pediatr Emerg Care
1991;7(3):163-5.
Physicians’ Desk Reference, Medical Economics Company, Montvale, NJ, 2002.
Silvasti M, Karttunen P, Tukiainen H, Kokkonen P, Hanninen U, Nykanen S.
Pharmacokinetics of dextromethorphan and dextrorphan: a single dose comparison of
three preparations in human volunteers. Int J Clin Pharmacol Ther Toxicol
1987;25(9):493-7.
Zawertailo LA, Kapla HL, Busto UE, Tyndale RF, Sellers EM. Psychotropic effects of
dextromethorphan are altered by the CYP2D6 polymorphism: a pilot study. J Clin
Psychopharmacol 1998;18(4):332-7.
- 28 -

Diazepam
Diazepam is a colorless, crystalline compound. Available primarily in tablet or liquid
form.
Synonyms: 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one;
Valium®, Valrelease®, Vazepam®, Diaz Intensol®, Diastat®, Dizac®.
Sources: Diazepam is a Schedule IV controlled substance and is available by
prescription in tablet, gel and injectable form. Valium® tablets are white (2 mg), yellow
(5 mg) or blue (10 mg) round tabs with a cut out “V” design. Valium® Injectable is
available in 5 mg/mL strength liquid.
Drug Class: Tranquilizer, sedative, CNS depressant.
Medical and Recreational Uses: Used medicinally in the management of anxiety
disorders, as an adjunct for the relief of skeletal muscle spasm and for convulsive
disorders/status epilepticus, and as a minor tranquilizer or sedative. Also used to suppress
or dampen acute alcohol withdrawal, and anxiety-related gastrointestinal disorders such
as stress ulcers. Diazepam is used recreationally as a sedative or to enhance the effects of
alcohol or opioids. For example, administration of diazepam 30 minutes after a dose of
oral methadone reportedly produces an augmented high. Diazepam is used by cocaine
users to increase seizure threshold and by heroin users to enhance the effects of heroin,
and by both of these users to reduce the impact of withdrawal symptoms between doses.
Potency, Purity and Dose: Commonly prescribed doses of Valium® are 5-40 mg daily.
For anxiety, 2-10 mg is taken twice to four times daily; for alcohol withdrawal symptoms
10 mg is taken three to four times daily. For the injectable form, 2-20 mg is administered
intramuscularly or intravenously. Street doses may consist of several tablets administered
at once.
Route of Administration: Usually oral, but intravenous injection is possible after
preparing a solution from crushed tablets. Commercially available liquid Valium® can be
injected, and gel forms can be rectally administered.
Pharmacodynamics: Diazepam is a 1,4-benzodiazepine, which binds with high affinity
to the GABA A receptor in the brain to reduce arousal and to affect emotions. Diazepam’s
action causes an increase in affinity of the major inhibitory neurotransmitter, GABA.
GABA binds mainly to the α subunit while diazepam binds to the β subunit. The γ
subunit is also essential for modulation of chloride transport by benzodiazepines.
Diazepam increases chloride transport through ion-channels and ultimately reduces the
arousal of the cortical and limbic systems in the CNS. Diazepam depresses the electrical
after-discharge in the amygdala and hippocampus regions of the limbic system that affect
emotions.
Pharmacokinetics: Diazepam is rapidly absorbed. Oral bioavailability is approximately
100%, and close to 99% is bound in plasma. The half-life of diazepam is 43±13 hours,
- 29 -

ut ranges from 40-100 hours if the contribution from active metabolites is included.
Diazepam is metabolized to nordiazepam which is an active metabolite with a half-life of
40-99 hours. Temazepam and oxazepam are minor active metabolites of diazepam.
Diazepam is excreted in urine mainly as oxazepam conjugate (~33 %), and temazepam
conjugate, with only traces of diazepam and nordiazepam.
Molecular Interactions / Receptor Chemistry: Diazepam is demethylated to
nordiazepam via P450 2C19 and 3A4; and 3-hydroxylation to temazepam and oxazepam
occurs via P450 3A4. Potential inhibitors of 2C19 and 3A4 could decrease the rate of
diazepam elimination if administered concurrently, while potential inducers of these
isoenzymes could increase the rate of elimination.
Blood to Plasma Concentration Ratio: 0.55 and 0.70 reported; 0.59 for nordiazepam.
Interpretation of Blood Concentrations: Simple interpretation of blood concentrations
without any knowledge of drug-taking history is ill advised. Given changing responses
with repeated use and variability in response, blood concentrations will not provide a
good indication of likely behavioral effects. Additionally, the long half-life of diazepam
may cause accumulation to occur with repeated use. Blood concentrations may be
several-fold higher after chronic use compared to single use, and there are significant
increases in blood levels in the elderly
Therapeutic blood concentrations typically range from 0.1-1.0 mg/L. Single oral
doses of 10 mg result in diazepam concentrations of 0.2-0.6 mg/L at 0.5-2 hours, while
chronic doses of 30 mg produce steady state diazepam concentrations of 0.7-1.5 mg/L
and nordiazepam concentrations of 0.35-0.53 mg/L. Plasma concentrations of 0.3-0.4
mg/L are recommended for anxiolytic effects, and > 0.6 mg/L for control of seizures.
Higher concentrations might suggest misuse or abuse.
Interpretation of Urine Test Results: Urine concentrations of metabolites are detectable
for several days to weeks after last use. Urinary excretion of unchanged drug is less than
1%.
Effects: At low doses, diazepam is a moderate tranquilizer, causing sleepiness,
drowsiness, confusion, and some loss of anterograde memory. At high doses, excitement,
disinhibition, severe sedation, and effects on respiration occur, particularly if respiration
is impaired by other drugs or by disease. Diazepam can produce a state of intoxication
similar to that of alcohol, including slurred speech, disorientation, and drunken behavior.
Side Effect Profile: Side effects may include dry mouth, blurred or double vision,
headache, vertigo, urinary retention, excessive perspiration, nausea and vomiting, ataxia,
tremor, depression, hypotension and diminished reflexes. The elderly are more likely to
develop significant adverse CNS effects from the use of diazepam. In overdose,
paradoxical reactions of anxiety, insomnia, stimulation, hallucination, and acute
hyperexcited state may occur. Shallow breathing, clammy skin, dilated pupils, weak and
rapid pulse, coma, and death are possible.
- 30 -

Duration of Effects: Dose-dependent, however, with therapeutic doses onset of effects
occurs within 30 minutes and significant effects can last for 12-24 hours.
Tolerance, Dependence and Withdrawal Effects: Regular use will produce tolerance to
most of the sedative and adverse effects, but tolerance may not occur for the anxiolytic
benefits of diazepam. Tolerance may take several weeks or months to develop depending
on dose and frequency of administration. Diazepam is capable of causing mild physical
and psychological dependence and is regarded as having a significant abuse potential.
Abstinence or abrupt withdrawal may produce excitement, restlessness, dysphoria,
anxiety, apprehension, fearfulness, dizziness, headache, muscle stiffness, tremors,
insomnia, and sensitivity to light and sound. More severe symptoms may include intense
rebound nausea, vomiting, abdominal cramps, delirium, hallucinations, hyperthermia,
sweating, panic attacks, confusional or paranoid psychoses, tachycardia, increased blood
pressure, and occasionally seizures or convulsions.
Drug Interactions: Other benzodiazepines, alcohol, phenothiazines, narcotic analgesics,
barbiturates, MAOI’s, and other CNS depressants may potentiate action of diazepam.
Alcohol enhances such effects as drowsiness, sedation, and decreased motor skills, and
can also exacerbate the memory impairing effects of diazepam. Cimetidine delays
clearance of diazepam. Valproate may potentiate the CNS depressant effects.
Theophylline has an antagonistic action to some of the deleterious effects of diazepam.
Performance Effects: Laboratory studies have shown that single doses of diazepam (5-
20 mg) are capable of causing significant performance decrements, with maximal effect
occurring at approximately 2 hour post dose, and lasting up to at least 3-4 hours.
Decreases in divided attention, increases in lane travel, slowed reaction time (auditory
and visual), increased braking time, decreased eye-hand coordination, and impairment of
tracking, vigilance, information retrieval, psychomotor and cognitive skills have been
recorded. Lengthened reaction times have been observed up to 9.5 hours post dose.
Lethargy and fatigue are common, and diazepam increases subjective perceptions of
sedation. Such performance effects are likely to be exacerbated in the elderly. In drug
users, diazepam has greater behavioral changes, including subjects’ rating of liking and
decrements in psychomotor and cognitive performance. Reduced concentration, impaired
speech patterns and content, and amnesia can also be produced, and diazepam may
produce some effects that may last for days. Laboratory studies testing the effect of
ethanol on subjects already using benzodiazepines demonstrate further increases in
impairment of psychomotor and other driving skills, compared to either drug alone.
Effects on Driving: The drug manufacturer suggests patients treated with diazepam be
cautioned against engaging in hazardous occupations requiring complete mental alertness
such as driving a motor vehicle. Simulator and driving studies have shown that diazepam
produces significant driving impairment over multiple doses. Single doses of diazepam
can increase lateral deviation of lane control, reduce reaction times, reduce ability to
perform multiple tasks, decrease attention, adversely effect memory and cognition, and
increase the effects of fatigue. Significant impairment is further increased when diazepam
is combined with low concentrations of alcohol (0.05 g/100 mL). A number of
- 31 -

epidemiological studies have been conducted to evaluate the risk of crashes associated
with the use of diazepam and other benzodiazepines. These show a range of relative risk,
but most demonstrate increases in risk compared to drug free drivers. These increases
have been twice to several fold. The elderly may have an increased risk of a motor
vehicle crash.
DEC Category: CNS depressant
DEC Profile: Horizontal gaze nystagmus present; vertical gaze nystagmus present in
high doses; lack of convergence present; pupil size normal; reaction to light slow; pulse
rate down; blood pressure down; body temperature normal. Other characteristic
indicators may include behavior similar to alcohol intoxication without the odor of
alcohol, staggering and stumbling, lack of balance and coordination, slurred speech,
disorientation, and poor performance on field sobriety tests.
Panel’s Assessment of Driving Risks: The incidences of diazepam in drivers involved
in road crashes and in drivers suspected of being under the influence, suggest an adverse
effect of diazepam on road safety. Data are available to demonstrate that single
therapeutic doses of diazepam can significantly impair psychomotor skills associated
with safe driving, with some effects still observable the morning after a nighttime dose.
References and Recommended Reading:
Baselt RC. Drug effects on psychomotor performance. Biomedical Publications, Foster
City, CA; pp 127-36; 2001.
de Gier JJ, Hart BJ, Nelemans FA, Bergman H. Psychomotor performance and real
driving performance of outpatients receiving diazepam. Psychopharmacology
1981;73(4):340-4.
Drummer OH. Benzodiazepines - Effects on Human Performance and Behavior. Forens
Sci Rev 2002;14(1/2):1-14.
Korttila K, Linnoila M. Psychomotor skills related to driving after intramuscular
administration of diazepam and meperidine. Anesthesiology 1975;42(6):685-91.
Korttila K, Linnoila M. Recovery and skills related to driving after intravenous sedation:
dose- response relationship with diazepam. Br J Anaesth 1975;47(4):457-63.
Kozena L, Frantik E, Horvath M. Vigilance impairment after a single dose of
benzodiazepines. Psychopharmacol (Berl) 1995;119(1):39-45.
Mattila MJ, Aranko K, Kuitunen T. Diazepam effects on the performance of healthy
subjects are not enhanced by treatment with the antihistamine ebastine. Br J Clin
Pharmacol 1993;35(3):272-7.
Mattila MJ, Palva E, Seppala T, Ostrovskaya RU. Actions and interactions with alcohol
of drugs on psychomotor skills: comparison of diazepam and gamma-hydroxybutyric
acid. Arch Int Pharmacodyn Ther 1978;234(2):236-46.
Morland J, Setekleiv J, Haffner JF, Stromsaether CE, Danielsen A, Wethe GH. Combined
effects of diazepam and ethanol on mental and psychological functions. Acta
Pharmacol Toxicol 1974;34(!):5-15.
Moskowitz H, Smiley A. Effects of chronically administered buspirone and diazepam on
driving- related skills performance. J Clin Psychiatry 1982;43(12 Pt 2):45-55.
- 32 -

O'Hanlon JF, Haak TW, Blaauw GJ, Riemersma JB. Diazepam impairs lateral position
control in highway driving. Science 1982;217(4554):79-81.
O'Hanlon JF, Vermeeren A, Uiterwijk MM, van Veggel LM, Swijgman HF. Anxiolytics'
effects on the actual driving performance of patients and healthy volunteers in a
standardized test. An integration of three studies. Neuropsychobiology 1995;31(2):81-
8.
Physicians’ Desk Reference, Medical Economics Company, Montvale, NJ, 2002.
Seppala K, Korttila K, Hakkinen S, Linnoila M. Residual effects and skills related to
driving after a single oral administration of diazepam, medazepam or lorazepam. Br J
Clin Pharmacol 1976;3(5):831-41.
Smiley A, Moskowitz H. Effects of long-term administration of buspirone and diazepam
on driver steering control. Am J Med 1986;80(3B):22-9.
van Laar MW, Volkerts ER, van Willigenburg AP. Therapeutic effects and effects on
actual driving performance of chronically administered buspirone and diazepam in
anxious outpatients. J Clin Psychopharmacol 1992;12(2): 86-95.
Willumeit HP, Ott H, Neubert W, Hemmerling KG, Schratzer M, Fichte K. Alcohol
interaction of lormetazepam, mepindolol sulphate and diazepam measured by
performance on the driving simulator. Pharmacopsychiatry 1984;17(2):36-43.
- 33 -

- 34 -

Diphenhydramine
Diphenhydramine is a white, crystalline powder. Available primarily in tablet, capsule
and liquid form.
Synonyms: 2-(diphenylmethoxy)-N,N-dimethylethylamine hydrochloride;
diphenhydramine hydrochloride; Benadryl®, Unisom® Sleepgels, Dytuss®,
Dramamine®.
Source: Available in capsules, tablets, chewable tablets, syrups, elixirs, topical, and
injectable forms in a variety of prescription and over-the-counter medications. Products
contain diphenhydramine alone or in combination with other drugs such as
pseudoephedrine and acetaminophen. Diphenhydramine is also an ingredient in several
Tylenol® (i.e., acetaminophen) preparations. Dimenhydrinate (Dramamine®) is a
combination of diphenhydramine and 8-chlorotheophylline in equal molecular
proportions.
Drug Class: Antihistamine, antiemetic, sleep aid, sedative, CNS depressant.
Medical and Recreational Uses: Used as an antihistamine for the temporary relief of
seasonal and perennial allergy symptoms. Diphenhydramine is also used as a sleep aid
and a cough suppressant, and has been used as a centrally acting antitussive although the
mechanism for this action is unclear. Dramamine is used as a prophylaxis against and for
the treatment of motion sickness.
Potency, Purity and Dose: As an antihistamine, recommended doses for adults is 25-50
mg diphenhydramine every 6-8 hours, not to exceed 50-100 mg every 4-6 hours. For
children, 12.5-25 mg three or four times daily is recommended. As a sleep aid the dose is
50 mg at bedtime. Adults can be given 10-50 mg intravenously or intramuscularly, up to
a maximum daily dose of 400 mg.
Route of Administration: Oral, injected, and topical applications.
Pharmacodynamics: Diphenhydramine is a first generation antihistamine and is a H 1
receptor antagonist. Antagonism is achieved through blocking the effect of histamine
more than blocking its production or release. Diphenhydramine inhibits most responses
of smooth muscle to histamine and the vasoconstrictor effects of histamine. The
antagonism may also produce anticholinergic effects, antiemetic effects, and significant
sedative side effects.
Pharmacokinetics: Following oral administration diphenhydramine is well absorbed
from the gastrointestinal tract, is widely distributed throughout the body, and is able to
pass though the blood-brain barrier. The oral availability is 61%, and 78% is bound in
plasma. Peak plasma concentrations are reached in 2-3 hours. Diphenhydramine is
metabolized to nordiphenhydramine (active metabolite), dinordiphenhydramine, and
diphenylmethoxyacetic acid. The plasma half-life is 8.5±3.2 hours; shorter and longer
- 35 -

half-lives have been reported for children and elderly subjects, respectively. Urinary
excretion of unchanged diphenhydramine is 1.9%.
Molecular Interactions / Receptor Chemistry: Diphenhydramine is metabolized via
cytochrome P450 2D6 isoenzyme. Potential inhibitors of P450 2D6 could decrease the
rate of drug elimination if administered concurrently, while potential inducers could
increase the rate of drug elimination.
Blood to Plasma Concentration Ratio: 0.77 and 0.82 reported.
Interpretation of Blood Concentrations: Following a single oral dose of 50 mg,
average peak plasma concentrations of 83 ng/mL diphenhydramine were detected at 3
hours, declining to 9 ng/mL by 24 hours. A single oral 100 mg dose resulted in average
peak plasma concentrations of 112 ng/mL at 2 hours post dose. Effective antihistamine
concentrations are greater than 25 ng/mL, drowsiness can be observed at 30-40 ng/mL,
and mental impairment may be observed with concentrations above 60 ng/mL.
Interpretation of Urine Test Results: Less than 2% of an oral dose is excreted in the 24
hour urine as unchanged parent drug, while approximately 11% is eliminated as its
glucuronide conjugate.
Effects: First generation H 1 antagonists can both stimulate and depress the CNS.
Stimulation results in restlessness, nervousness and inability to sleep, while depressive
effects include diminished alertness, slowed reaction time and somnolence.
Diphenhydramine is particularly prone to cause marked sedation. Drowsiness, reduced
wakefulness, altered mood, impaired cognitive and psychomotor performance may also
be observed.
Side Effect Profile: Includes agitation, anticholinergic side effects such as dry mouth,
confusion, dizziness, drowsiness, fatigue, disturbed coordination, irritability, paresthesia,
blurred vision, and depression. In overdose, symptoms may include excitement, ataxia,
tremor, sinus tachycardia, fever, hallucination, athetosis, convulsions or seizures,
hypotension, deep coma, cardiorespiratory collapse, and death. Fixed and dilated pupils
are also observed. Gastrointestinal symptoms are less with diphenhydramine than with
other H 1 antagonists.
Duration of Effects: Dose-dependent, however, following oral administration of
therapeutic doses, peak plasma concentrations are reached in 2-3 hours and effects
usually last 4-6 hours.
Tolerance, Dependence and Withdrawal Effects: Some tolerance may develop to the
sedative effects of diphenhydramine with repeated oral dosing. No reported dependence
or withdrawal effects with doses recommended.
Drug Interactions: Effects of diphenhydramine are increased by the presence of
alcohol, MAOI’s, diazepam, hypnotics, sedatives, tranquilizers, and other CNS
- 36 -

depressants. Alcohol enhances such effects as drowsiness, sedation and decreased motor
skills. These decrements in effect are more pronounced in the elderly.
MAOI’s prolong and intensify the anticholinergic effects of diphenhydramine.
Performance Effects: All first generation antihistamines, including diphenhydramine,
have been demonstrated to diminish cognitive and psychomotor performance in healthy
volunteers. Impairment might even be of greater clinical significance in patients when the
allergic disorder per se adversely affects CNS function, as suggested in studies in which a
reduction in cognitive functioning in patients was exacerbated by diphenhydramine.
Laboratory studies have shown diphenhydramine to decrease alertness, decrease reaction
time, induce somnolence, impair concentration, impair time estimation, impair tracking,
decrease learning ability, and impair attention and memory within the first 2-3 hours post
dose. Significant adverse effects on vigilance, divided attention, working memory, and
psychomotor performance have been demonstrated. It is important to note that
impairment has been shown to occur even in the absence of self-reported sleepiness or
sedation. Concurrent use of diazepam and diphenhydramine caused significant
performance decrements at 2 hours, and to some degree up to 4 hours.
Effects on Driving: The drug manufacturer states that patients should be warned about
engaging in activities requiring mental alertness such as driving a car. Diphenhydramine
has repeatedly been shown to severely impair tracking and reaction time performance in
actual on-the-road driving tests. Single doses of 50 mg have been shown to cause
significant impairment during a 90 km highway test (measuring vehicle following,
constant speed and lateral position). In contrast, single 25-100 mg doses caused no
significant driving effects during a short 15 minute driving test. Using the Iowa Driving
Simulator, Weiler et al, 2000 compared the effects of a single oral dose of 50 mg
diphenhydramine to the effects corresponding to a blood alcohol concentration of 0.1
g/100 mL. Diphenhydramine caused significantly less coherence (ability to maintain a
constant distance) and impaired lane keeping (steering instability and crossing center
line) compared to alcohol. Overall driving performance was the poorest after taking
diphenhydramine, and participants were most drowsy after taking diphenhydramine
(before and after testing). The authors concluded that diphenhydramine clearly impairs
driving performance, and may have an even greater impact than does alcohol on the
complex task of operating a motor vehicle.
DEC Category: CNS depressant
DEC Profile: Data not available; however, the profile for a CNS depressant is:
horizontal gaze nystagmus present; vertical gaze nystagmus present at high doses; lack of
convergence present; pupil size normal; reaction to light slow; pulse rate normal; blood
pressure normal; body temperature normal. Diphenhydramine may produce dilated
pupils.
Panel’s Assessment of Driving Risks: Single therapeutic doses of diphenhydramine
have been shown to significantly impair psychomotor performance during the first 4
hours, and may have a greater impact on driving performance than alcohol.
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References and Recommended Reading:
Baselt RC. Drug effects on psychomotor performance. Biomedical Publications, Foster
City, CA; pp 137-43;2001.
Burns M, Wilkinson C. Laboratory study of drug-related performance changes. J Occup
Med 1990;33(4): 320-6.
Drug Facts and Comparisons. Facts and comparisons, Saint Louis, MO; 1996.
Friedel B, Joo S, Reker K, Kadding W, Klostermann P, Saternus KS, Schneider V. Test
drivers in the Daimler-Benz driving simulator with drivers under diphenhydramine.
DOT HS 807 688 pp 1-162; 1991.
Gengo FM, Manning C. A review of the effects of antihistamines on mental processes
related to automobile driving. J Allergy Clin Immunol 1990;86:1034-9.
Gengo F, Gabos C, Miller JK. The pharmacodynamics of diphenhydramine-induced
drowsiness and changes in mental performances. Clin Pharmacol Ther 1989;45:15-21.
Hardman JG, Limbird LE (ed’s). Goodman & Gilman’s The Pharmacological Basis of
Therapeutics. McGraw-Hill, NY, NY; 1996.
Moskowitz H, Burns M. Effects of terfenadine, diphenhydramine, and placebo on skills
performance. Cutis 1988;42(4A):14-8.
O’Hanlon JF, Ramaekers JG. Antihistamine effects on actual driving performance in a
standard test: a summary of Dutch experience, 1989-94. Allergy 1995;50:234-42.
Physicians’ Desk Reference, Medical Economics Company, Montvale, NJ, 2002.
Ramaekers JG, O'Hanlon JF. Acrivastine, terfenadine and diphenhydramine effects on
several aspects of actual driving performance as a function of dose and time after
dosing. Eur J Clin Pharmacol 1994;42:363-9.
Ramaekers JG. Behavioral toxicity of medicinal drugs. Drug Safety 1998;18:189-208.
Rice VJ, Snyder HL. The effects of benadryl and hismanal on psychomotor performance
and perceived performance. Aviat Space Environ Med 1993;64:726-34.
Simons FER. H1 receptor antagonists. Comparative tolerability and safety. Drug Safety
1994;10:350-80.
Vuurman EFPM, Van Veggel LMA, Uiterwijk MMC, Leutner D, O'Hanlon JF. Effects
of semprex-D and diphenhydramine on learning in young adults with seasonal allergic
rhinitis. Allergy Asthma Immunol 1993;76:247-52.
Weiler JM, Bloomfield JR, Woodworth GG, Grant AR, Layton TA, Brown TL,
McKenzie DR, Baker TW, Watson GS. Effects of fexofenadine, diphenhydramine,
and alcohol on driving performance. A randomized, placebo-controlled trial in the
Iowa Driving Simulator. Ann Intern Med 2000;132(5):354-63.
Witek TJ Jr, Canestrari DA, Miller RD, Yang JY, Riker DK. Characterization of daytime
sleepiness and psychomotor performance following H1 receptor antagonists. Allergy
Asthma Immunol 1995;74(5):419-26.
- 38 -

Gamma-Hydroxybutyrate (GHB, GBL, and 1,4-BD)
GHB is a clear liquid, or a white powder with a soap-like texture. Precursor drugs such as
gamma-butyrolactone (GBL) and 1,4 butanediol (1,4-BD) are clear liquids.
Synonyms:
GHB: Sodium oxybate, Xyrem® oral solution; liquid X, liquid XTC, salt water, scoop,
soap, grievous bodily harm, georgia home boy, G, G-caps, easy lay, everclear,
vita G, degreaser + lye, smart drug, gamma-OH, Somatomax.
GBL: 2(3)-furanone dihydro; Blue Nitro, G3, Invigorate, Jolt, ReActive, REMForce,
RenewTrient, Rest-eze, Revivarant, Verve, V35.
1,4-BD: tetramethylene glycol; Amino Flex, Enliven, FX, GHRE, Inner G, NRG3,
Pine Needle Extract, Revitalize, Serenity, SomatoPro, Thunder Nectar, Zen.
Source: GHB was first synthesized in 1960 as an experimental GABA analog, and was
classified as a food and dietary supplement and sold in health food stores in early 1990. It
was available in tablet, capsule and liquid forms. In late 1990, the FDA banned over-thecounter
sales of GHB in the U. S. In 1999, the FDA issued warnings on the dangers of its
precursor drugs GBL and 1,4-BD. In early 2000, GHB was federally reclassified as a
Schedule 1 controlled substance. GBL and 1,4-BD are not scheduled, however, GBL is
classified as a list 1 chemical and a controlled substance analog, while 1,4-BD is listed as
a controlled substance analog. GHB can be clandestinely made and the ingredients are
available in kit form over the internet. GHB is made from GBL and a base (e.g.
lye/NaOH), the mixture is heated, and vinegar is added to reduce the pH. Acetone can
then be added and the mixture dried, resulting in GHB powder. GBL and 1,4-BD are
commercially available as industrial solvents and are used as ingredients in cleaners,
solvents, paint removers, and engine degreasers. They are also sold as “natural
supplements” over the internet, and in some health food stores and gymnasiums, and are
marketed as natural, non-toxic dietary supplements.
Drug Class: CNS depressant, sedative, anesthetic.
Medical and Recreational Uses: In Europe, GHB is used as an anesthetic adjunct and
hypnotic agent, used to treat narcolepsy, and used to suppress symptoms of alcoholdependence
and opiate withdrawal syndrome. In the U. S., medically formulated sodium
oxybate (Xyrem®) has been approved as a Schedule III controlled substance for the
treatment of cataplexy (sudden loss of muscle tone associated with narcolepsy).
Recreationally, GHB is used for its intoxicating effects (euphoria, reduced inhibitions,
sedation), and by bodybuilders as an alternative to anabolic steroids. GBL and 1,4-BD
rapidly convert to GHB within the human body following oral administration and are
taken as GHB substitutes. They are marketed as anti-aging drugs, for weight loss, to treat
insomnia, anxiety and depression, and as mood enhancers and energizers.
Potency, Purity and Dose: Clinical doses for alcohol withdrawal syndrome are 25-50
mg/kg every 12 hours (1.7-3.5 g/70 kg); sleep induction 20-30 mg/kg (1.5-2.25 g/70 kg);
prolonged deep sleep 75-100 mg/kg (5-7 g/70 kg); and anesthetic induction greater than
100 mg/kg (> 7 g/70 kg). Illicit manufacture often introduces impurities and wide
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variations in potency. Recreational use of GHB often involves doses well in excess of
one teaspoon (~2.5 g, or 35 mg/kg in a 70 kg adult) of the powder dissolved in
water/alcohol, or one capful of liquid GHB, GBL, or 1,4-BD; such doses far exceed
therapeutic doses. Chronic use can consist of dosing every few hours, around the clock,
for months to years. Up to 100 g GHB has been reportedly used by an individual in one
day. GHB and its precursor drugs are often used in combination with alcohol, MDMA,
marijuana, methamphetamine, and cocaine.
Route of Administration: Oral, intravenous.
Pharmacodynamics: GHB is a naturally occurring compound present in both
mammalian CNS and peripheral tissue. It is also a minor metabolite and precursor of the
major inhibitory neurotransmitter GABA. GHB is also the pharmacologically active form
of both GBL and 1,4-BD. GHB has weak agonist activity at GABA B receptors and there
appears to be a distinct GHB receptor site in the brain. GHB dose-dependently alters
dopaminergic activity; at sub-anesthetic doses there is an initial excitation of dopamine
neurons producing elevated levels of synaptic dopamine; at anesthetic doses GHB blocks
impulse flow from dopamine neurons resulting in a build-up of dopamine in the nerve
terminals. GHB mimics natural physiological sleep, enhances REM sleep, and increases
stage 3 and 4 of slow-wave sleep. GHB decreases alcohol consumption and intensity of
withdrawals. Beyond the CNS effects, GHB has significant cardiovascular
pharmacology, causing bradycardia and dysregulation of blood pressure (hyper- and
hypotension). Interestingly, GHB causes a detectable increase in growth hormone and
prolactin concentrations with doses as small as 3 g, and this is the basis for its use in body
building despite there being no evidence of an actual increase in body mass.
Pharmacokinetics: Oral doses are rapidly absorbed from the gastrointestinal tract and
exhibit first pass metabolism. Absorption is capacity limited (an increase in dose results
in increased time to peak concentration). There is an increased rate of absorption of GHB
on an empty stomach leading to a decreased time to peak concentration and an increased
concentration. Accumulation is not known to occur following repeated doses. GHB
readily crosses the blood-brain barrier and placental barrier, and is distributed in the
brain, cerebrospinal fluid, vitreous, liver, and kidney. The dose-response curve is steep,
and a large between and within subject variability is noted. GHB is rapidly eliminated
and has a half-life of 27 minutes (range 20-53 minutes) which appears to increase with
higher doses, a sign of zero order or saturation kinetics. GHB is metabolized to succinic
semialdehyde (SSA) via GHB-dehydrogenase, then to succinic acid via SSAdehydrogenase.
GBL is metabolized to GHB via lactonase; while 1,4-BD is first
metabolized to γ-hydroxybutyraldehyde via alcohol dehydrogenase, then to GHB via
aldehyde dehydrogenase.
Molecular Interactions / Receptor Chemistry: Metabolism via cytochrome P450
isoenzymes has not been described.
Blood to Plasma Concentration Ratio: 1.2 (N=1)
- 40 -

Interpretation of Blood Concentrations: Peak plasma concentrations are observed at
20-45 minutes. Due to rapid elimination, GHB is undetectable in plasma or blood after
6-8 hours. Following single oral doses of 25 mg/kg GHB in 10 alcoholic dependant
patients, mean peak plasma GHB concentrations were 54 mg/L (24-88 mg/L). Single oral
doses of 12.5, 25, and 50 mg/kg in 8 healthy subjects produced mean peak plasma GHB
concentrations of 23, 46 and 80 mg/L, respectively. Single oral doses of 26-52 mg/kg in 6
narcoleptic patients resulted in mean peak plasma GHB concentrations of 63 mg/L (30-
102 mg/L). The same doses were administered to the same subjects 4 hours later, and the
mean peak GHB concentrations obtained were 91 mg/L (47-125 mg/L). An intravenous
dose of 50 mg/kg in an adult produced a peak blood GHB concentration of approximately
170 mg/L within 15 minutes. Patients presenting to an emergency department with GHB
overdose/intoxication, had blood GHB concentrations ranging from 29-432 mg/L (mean
118 mg/L; N = 54).
Although GHB is naturally present in the human body, endogenous blood GHB
concentrations are typically well below 1 mg/L in living subjects. In contrast, endogenous
postmortem production of GHB can occur, and concentrations of up to 170 mg/L GHB
have been reported in non-GHB using subjects. In postmortem analysis the analysis of
multiple specimens such as vitreous and urine is recommended.
Interpretation of Urine Test Results: Peak urine concentrations are observed within 4
hours of administration and GHB is undetectable in urine after 10-12 hours. Endogenous
concentrations of up to ~7 mg/L GHB have been detected in urine of non-GHB using
subjects. It is suggested that a cut-off for urinary GHB be set at 10 mg/L. Similarly, in
postmortem urine specimens from non-GHB using subjects, urine concentrations of GHB
are typically below 10 mg/L.
Effects:
Psychological: At low doses, effects are similar to those seen with alcohol. Effects
include relaxation, reduced inhibitions, euphoria, confusion, dizziness, drowsiness,
sedation, inebriation, agitation, combativeness, and hallucinations.
Physiological: Nausea, vomiting, profuse sweating, somnolence, visual disturbances,
nystagmus, loss of peripheral vision, short-term amnesia, uncontrolled shaking or
seizures, bradycardia, hypothermia, suppression of gag reflex, respiratory depression, and
transient or unarousable unconsciousness.
Side Effect Profile: Disorientation, sweating, vomiting, incontinence, apnea, severe
ataxia, sinus bradycardia, twitching, seizure-like activity and hypothermia. In overdose,
symptoms may include severe respiratory depression, mild acute respiratory acidosis,
sinus bradycardia or sinus tachycardia, suppression of gag reflex, acute delirium,
combativeness, unarousable unconsciousness, coma, and patients often need to be
intubated. Deaths have been reported following overdose from GHB, GBL and 1,4-BD
alone, and in combination with other drugs.
Duration of Effects: Onset of effects occurs within 10-20 minutes, peak plasma
concentrations are achieved within 20-45 minutes, and effects generally last 2-5 hours.
Complete recovery from GHB overdose can occur within 3-6 hours. Sleep induction time
- 41 -

is shortest with GBL and longest with 1,4-BD, as GBL is more lipophilic and is absorbed
faster. There is a longer duration of effect following 1,4-BD ingestion as it metabolizes
more slowly to GHB than does GBL.
Tolerance, Dependence and Withdrawal Effects: Tolerance can develop to GHB with
chronic abuse and even following chronic treatment. Subjects do not become tolerant to
all the effects (e.g. tolerance does not develop to the enhanced sleep that GHB produces).
Cross-tolerance exists between GHB and ethanol. Severe physical and psychological
addiction occurs with chronic abuse. Clinical presentation of withdrawal may include
mild clinical anxiety, confusion, agitation, tremor, muscular cramps, insomnia,
combativeness, delirium, delusions, paranoia with hallucinations (auditory, tactile and
visual), tachycardia, hypotension, and an occasional schizophrenic-like state. The
withdrawal syndrome can start as early as 1-2 hours after the last dose in addicted
individuals.
Drug Interactions: Potential additive effects between GHB and other sedating CNS
depressants, including alcohol, antidepressants, antipsychotics, antihistamines and muscle
relaxants. In rats, ethanol has significant synergistic effects on the sedative, behavioral
and toxic effects of GHB, GBL and 1,4-BD. Ethanol also delays the conversion of 1,4-
BD to GHB, because both 1,4-BD and ethanol utilize alcohol-dehydrogenase in their
metabolic pathways. Several drugs have been shown to inhibit GHB-dehydrogenase and
it is not known clinically what effects these drugs would have if administered
concurrently. These drugs include valproate, ethosuximide, salicylate, amobarbital,
phenytoin, disulfiram and cyanide.
Performance Effects: Oral GHB doses of 1-2 g have been shown not to deteriorate
reactive, attentive and co-ordination skills related to driving, nor increase the effects of
low dose alcohol. Similarly, oral doses of 12.5-25 mg/kg GHB had no effect on attention,
vigilance, alertness, short-term memory or psychomotor coordination; although dizziness
or dullness were experienced in 50-66% of subjects. It is important to note, however, that
doses used in laboratory studies to date have been well below both recreational and
abused doses of GHB.
Effects on Driving: Signs of behavioural effects and impaired performance have been
reported in several driving case reports. In 13 driving under the influence cases where
GHB was detected, the reported symptoms were generally those of a CNS depressant.
The subjects were typically stopped because of erratic driving, such as weaving, ignoring
road signs, and near-collisions. Common signs of impairment included confusion and
disorientation, incoherent speech, short-term memory loss, dilated pupils, lack of balance
and unsteady gait, poor coordination, poor performance of field sobriety tests, copious
vomiting, unresponsiveness, somnolence, and loss of consciousness. GHB concentrations
in blood specimens collected between 1-3.5 hours of the arrest ranged from 26-155 mg/L
(median 95 mg/L). In another 11 cases of driving under the influence of GHB,
concentrations of GHB in blood and urine specimens ranged from 81-360 mg/L and 780-
2380 mg/L, respectively. Circumstances of their arrest, observed driving behavior and
signs of impairment were similar to the previous study. Other reported symptoms have
- 42 -

included dizziness, drowsiness, agitation, loss of peripheral vision, slow responses, slow
and slurred speech, and transient unconsciousness.
DEC Category: CNS depressant
DEC Profile: Horizontal gaze nystagmus present; vertical gaze nystagmus present in
high doses; lack of convergence present; pupil size generally dilated; reaction to light
slow; pulse rate normal; blood pressure normal; body temperature generally down. Other
characteristic indicators include vomiting, sweating, slurred speech, somnolence or
transient unconsciousness, poor balance and coordination, and poor performance on field
sobriety tests. Note that while pulse rate and blood pressure may decrease after GHB
ingestion, both parameters may be elevated during drug withdrawal.
Panel’s Assessment of Driving Risks: Given the ability of GHB to induce sleep and
unconsciousness, recreational use of GHB or its precursor drugs have the potential to
produce moderate to severe driving impairment.
References and Recommended Reading:
Baselt RC. Drug effects on psychomotor performance. Biomedical Publications, Foster
City, CA; pp 179-80;2001.
Chin RL, Sporer KA, Cullison B, Dyer JE, Wu TD. Clinical course of gammahydroxybutyrate
overdose. Ann Emerg Med 1998;31(6):716-22.
Couper FJ, Marinetti L. γ-Hydroxybutyrate (GHB) - Effects on Human Performance and
Behavior. Forens Sci Rev 2002;14(1/2):101-21.
Couper FJ, Logan BK. GHB and driving impairment. J Forens Sci 2001;46(4):919-23.
Dyer JE. γ-Hydroxybutyrate: A health-food product producing coma and seizurelike
activity. Am J Emerg Med 1991;9:321-4.
Dyer JE, Roth B, Hyma BA. Gamma-hydroxybutyrate withdrawal syndrome. Ann Emerg
Med 2001;37(2):147-53.
Ferrara SD, Zotti S, Tedeschi G, et al. Pharmacokinetics of gamma-hydroxybutyric acid
in alcohol dependent patients after single and repeated oral doses. Br J Clin
Pharmacol 1992;34(3):231-5.
Hoes MJAJM, Vree TB and Guelen PJM, Gamma-hydroxybutyric acid as hypnotic.
L’Encephale 6:93-99,1980.
Palatini P, Tedeschi G, Frison R, et al. Dose-dependent absorption and elimination of
gamma-hydroxybutyric acid in healthy volunteers. Eur J Clin Pharmacol
1993;45:353-6.
Scharf MB, Lai AA, Branigan B, et al. Pharmacokinetics of gammahydroxybutyrate
(GHB) in narcoleptic patients. Sleep 1998;21(5):507-14.
Stephens BG, Baselt RC. Driving under the influence of GHB J Anal Toxicol
1994;18:357-8.
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- 44 -

Ketamine
Ketamine is a white, crystalline powder or clear liquid.
Synonyms: (+/-)-2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone; Ketalar®,
Ketaject®, Ketaset®, Vetalar®; K, Special K, Vitamin K, Lady K, Jet, Super Acid,
Bump, Special LA Coke, KitKat, Cat Valium.
Source: Available by prescription only, and is commercially available as a veterinary
anesthetic. It is difficult to synthesize clandestinely and is usually stolen from
veterinarian offices or diverted from legitimate pharmaceutical sources in liquid form.
Ketamine is currently a schedule III controlled substance in the US.
Drug Class: Dissociative anesthetic, hallucinogen, psychotomimetic.
Medical and Recreational Uses: Primarily used in veterinary applications as a
tranquilizer. Also used as an anesthetic induction agent for diagnostic and surgical
procedures in humans, prior to the administration of general anesthetics. Occasionally
used as a short-acting general anesthetic for children and elderly patients. Recreationally
used as a psychedelic and for its dissociative effects.
Potency, Purity and Dose: Ketamine is available as a racemic mixture with the S-
(+)- isomer being more potent than the R-(-)- isomer. Commercially supplied as the
hydrochloride salt in 0.5 mg/mL and 5 mg/mL ketamine base equivalents. For induction
of 5-10 minutes surgical anesthesia, a dose of 1.0-4.5 mg/kg is intravenously
administered; 6.5-13 mg/kg is given intramuscularly for 12-25 minutes of surgical
anesthesia. The liquid from injectable solutions can be gently heated to evaporate the
water, leaving a white powder (ketamine hydrochloride) which can be snorted or orally
ingested. Recreational doses are highly variable. Common doses are 25-50 mg
intramuscularly, 30-75 mg snorting, and 75-300 mg oral. Snorting a small line (“bump”,
30-50 mg) usually results in a dreamy effect. “K-hole” can be obtained following a dose
of 60-125 mg intramuscularly, or by snorting 100-250 mg. Impurities are rarely seen,
although ketamine hydrochloride itself can be used as a heroin adulterant.
Route of Administration: Injected, snorted, orally ingested, and rectally administered.
Similar to phencyclidine (PCP), ketamine can be added to tobacco or marijuana cigarettes
and smoked.
Pharmacodynamics: Involves analgesia, anesthetic and sympathomimetic effects that
are mediated by different sites of action. Non-competitive NMDA receptor antagonism
is associated with the analgesic effects; opiate receptors may contribute to analgesia and
dysphoric reactions; and sympathomimetic properties may result from enhanced central
and peripheral monoaminergic transmission. Ketamine blocks dopamine uptake and
therefore elevates synaptic dopamine levels. Inhibition of central and peripheral
cholinergic transmission could contribute to induction of the anesthetic state and
hallucinations. Ketamine is structurally similar to PCP, but 10-50 times less potent in
blocking NMDA effects.
- 45 -

Pharmacokinetics: Bioavailability following an intramuscular dose is 93%, intranasal
dose 25-50%, and oral dose 20±7%. Ketamine is rapidly distributed into brain and other
highly perfused tissues, and is 12% bound in plasma. The plasma half-life is
2.3 ± 0.5 hours. Oral administration produces lower peak concentrations of ketamine, but
increased amounts of the metabolites norketamine and dehydronorketamine. Ketamine
and its metabolites undergo hydroxylation and conjugation. Norketamine produces
effects similar to those of ketamine. There are no significant differences between the
pharmacokinetic properties of the S-(+) and R-(-)-isomers.
Molecular Interaction / Receptor Chemistry: Cytochrome P450 3A4 is the principal
enzyme responsible for ketamine N-demethylation to norketamine, with minor
contributions from CYP2B6 and CYP2C9 isoforms. Potential inhibitors of these
isoenzymes could decrease the rate of ketamine elimination if administered concurrently,
while potential inducers could increase the rate of elimination
Blood to Plasma Concentration Ratio: Data not available.
Interpretation of Blood Concentrations: There is no direct correlation between
ketamine concentrations and behavior. Drowsiness, perceptual distortions and
intoxication may be dose related in a concentration range of 50 to 200 ng/mL, and
analgesia begins at plasma concentrations of about 100 ng/mL. During anesthesia, blood
ketamine concentrations of 2000-3000 ng/mL are used, and patients may begin to awake
from a surgical procedure when concentrations have been naturally reduced to 500-1000
ng/mL.
Interpretation of Urine Test Results: Urinary excretion of unchanged drug is 4±3%, and
ketamine use can be detected in urine for about 3 days. Concentration ranges for
ketamine in urine have been reported as low as 10 ng/mL and up to 25,000 ng/mL.
Effects: Users have likened the physical effects of ketamine to those of PCP, and the
visual effects to LSD.
Psychological: Decreased awareness of general environment, sedation, dream-like
state, vivid dreams, feelings of invulnerability, increased distractibility, disorientation,
and subjects are generally uncommunicative. Intense hallucinations, impaired thought
processes, out-of-body experiences, and changes in perception about body, surroundings,
time and sounds. Delirium and hallucinations can be experienced after awakening from
anesthesia.
Physiological: Anesthesia, cataplexy, immobility, tachycardia, increased blood
pressure, nystagmus, hypersalivation, increased urinary output, profound insensitivity to
pain, amnesia, slurred speech, and lack of coordination.
Side Effect Profile: High incidence of adverse effects, including anxiety, chest pain,
palpitations, agitation, rhabdomyolysis, flashbacks, delirium, dystonia, psychosis,
schizophenic-like symptoms, dizziness, vomiting, seizures, and paranoia.
- 46 -

Duration of Effects: Onset of effects is within seconds if smoked, 1-5 minutes if
injected, 5-10 minutes if snorted and 15-20 minutes if orally administered. Effects
generally last 30-45 minutes if injected, 45-60 minutes if snorted, and 1-2 hours
following oral ingestion. Ketamine is often readministered due to its relatively short
duration of action. Some subjects may experience dreams 24 hours later. Marked
dissociative effects, schizotypal symptoms and impaired semantic memory are found in
some recreational users days after drug use.
Tolerance, Dependence and Withdrawal Effects: In long-term exposure, high
tolerance, drug craving, and flashbacks are described. Little evidence of a physiological
withdrawal syndrome unless abrupt discontinuation in chronic users.
Drug Interactions: Midazolam attenuates altered perception and thought processes.
Lorazepam may decrease ketamine-associated emotional distress but does not decrease
cognitive or behavioral effects of ketamine. Acute administration of diazepam increases
the half-life of ketamine. Lamotrigine significantly decreases ketamine-induced
perceptual abnormalities, but increases the mood elevating effects. Haloperidol may
decrease impairment by ketamine in executive control functions, but does not affect
psychosis, perceptual changes, negative schizophrenic-like symptoms, or euphoria.
Alfentanil is additive to ketamine in decreasing pain and increasing cognitive
impairment. Physostigmine and 4-aminopyridine can antagonize some pharmacodynamic
effects of ketamine.
Performance Effects: Broad spectrum of cognitive impairments and marked
dissociative effects. Increased distractibility and intensely visual or polysensual
hallucinations. Impairment of immediate and delayed recall, and verbal declarative
memory. Memory impairment is associated with encoding or retrieval processes, and not
accounted for by decreased attention. Impaired language function, failure to form and use
memory traces of task relevant information. Overall decreased awareness, increased
reaction time, distorted perceptions of space, non-responsiveness, and blurred vision. The
S-(+) isomer impairs psychomotor function 3-5 times more than the R-(-) isomer.
Effects on Driving: The drug manufacturer suggests that patients should be cautioned
that driving an automobile should not be undertaken for 24 hours or more following
anesthesia. No driving studies have been performed.
DEC Category: Phencyclidine.
DEC Profile: Horizontal gaze nystagmus present; vertical gaze nystagmus present; lack
of convergence present; pupil size normal; reaction to light normal; pulse rate elevated;
blood pressure elevated; body temperature elevated. Other characteristic indicators may
include rigid muscles, cyclic behavior, and lack of response to painful stimuli.
Panel’s Assessment of Driving Risks: The use of ketamine is not conceivably
compatible with the skills required for driving due to its moderate to severe psychomotor,
cognitive, and residual effects.
- 47 -

References and Recommended Reading:
Adams VHA. The mechanisms of action of ketamine. Anaesthes Reanim 1998;23(3):60-
3.
Adler CM, Goldberg TE, Malhotra AK, Pickar D, Breier A. Effects of ketamine on
thought disorder, working memory, and semantic memory in healthy volunteers. Biol
Psychiat 1998;43(11):811-6.
Baselt RC. Drug effects on psychomotor performance. Biomedical Publications, Foster
City, CA; pp 199-200;2001.
Bowdle TA, Radan AD, Cowley DS, Kharasch ED, Strassman RJ, Roy-Byrne PP.
Psychedelic effects of ketamine in healthy volunteers: relationship to steady-state
plasma concentrations. Anesthesiology 1998;88(1):82-8.
Clements JA, Nimo WS, Grant IS. Bioavailability, pharmacokinetics and analgesic
activity of ketamine in humans. J Pharm Sci 1982;71(5):539-42.
Curran HV, Morgan CA. Cognitive, dissociative and psychotogenic effects of ketamine
in recreational users on the night of drug use and 3 days later. Addiction
2000;95(4):575-90.
Dotson JW, Ackerman DL, West LJ. Ketamine abuse. J Drug Issues 1995;25(4):751-7.
Ghoneim MM, Hinrichs JV, Mewaldt SP, Peterson RC. Ketamine: Behavioral effects in
subanesthetic doses. J Clin Psychopharm 1985;5(2):70-7.
Grant IS, Nimmo WS, Clements JA. (1981) Pharmacokinetics and analgesic effects of
i.m. and oral ketamine. Br J Anaesthes 1981;53(8):805-10.
Hartvig P, Valtysson J, Linder K-J, Kristensen J, Karlsten R, Gustafsswon LL, Persson J,
Svensson JO, Oye I, Antoni G, Westergerg G, Langstrom B. Central nervous system
effects of subdissociative doses of (S)-ketamine are related to plasma and brain
concentrations measured with positron emission tomography in healthy volunteers.
Clin Pharmac Ther 1995;58(2):165-73.
Hass DA, Harper DG. Ketamine: A review of its pharmacologic properties and use in
ambulatory anesthesia.
Anesth Prog 1992;39(3):61-8.
Hetem LSB, Danion JM, Diemujnsch P, Brandt C. Effect of a subanesthetic dose of
ketamine on memory and conscious awareness on healthy volunteers. Psychopharm
2000;152(3):283-8.
Idvall J, Ahlgren I, Aronsen KF, Stenberg P. Ketamine infusions: pharmacokinetics and
clinical effects. Br J Anaesth 1979;51:1167-73.
Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR,
Bowers MB Jr., Charney DS. Subanesthetic effects of noncompetitive NMDA
antagonist, ketamine, in humans. Arch Gen Psychiat 1994;51(3):199-214.
Malhotra AK, Pinals DA, Weingartner H, Sirocco K, Missar CD, Picker D, Breier A.
NMDA receptor function and human cognition: The effects of ketamine on healthy
volunteers. Neuropychopharm 1996;14(5):301-7.
Mozayani A. Ketamine - Effects on Human Performance and Behavior. Forens Sci Rev
2002;14(1/2):123-31.
Newcomer JW, Farber NB, Jevtovic-Todoroic V, Selke G, Melson AK, Hershey T, Craft
S, Olney JW. Ketamine-induced NMDA receptor hypofunction as a model of
memory impairment and psychosis. Neuropsychopharm 1999;20(2):106-18.
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Sethna NF, Liu M, Gracely R, Bennett GJ, Max MB. Analgesic and cognitive effects of
intravenous ketamine-alfentanil combinations versus either drug alone after
intradermal capsaicin in normal subjects. Anesth Analg 1998;86(6):1250-6.
Umbricht D, Schmid L, Koller R, Vollenweider FX, Hell D, Javitt DC. Ketamineinduced
deficits in auditory and visual context-dependent processing in healthy
volunteers: Implications for models for cognitive deficits in schizophrenia. Arch Gen
Psychiatry 2000;57(12):1139-47.
Weiner AL, Vierira L, McKay CA Jr., Bayer MJ. Ketamine abusers presenting to the
Emergency Department: A series of cases. J Emerg Med 2000;18(4):447-51.
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- 50 -

Lysergic acid diethylamide (LSD)
LSD is a white powder or a clear, colorless liquid.
Synonyms: d-lysergic acid diethylamide; acid, animal, barrels, beast, blotter, ‘cid, dots,
kool aid, LSD-25, lysergide, microdots, panes, sandoz, tabs, trips, white lightning,
window panes.
Source: LSD is manufactured from lysergic acid which occurs naturally in the ergot
fungus that grows on wheat and rye. It is a Schedule I controlled substance, available in
liquid, powder, tablet (microdots), and capsule form. The liquid is often applied to blotter
paper squares (frequently with colorful designs), stickers, sugar cubes, candy, or soda
crackers. LSD is also available in dropper bottles or in the form of gelatin sheets/shapes
(window panes).
Drug Class: Hallucinogen, psychedelic, psychotomimetic.
Medical and Recreational Uses: No medicinal use. Recreationally used as a
hallucinogen and for its ability to alter human perception and mood.
Potency, Purity and Dose: The strength of illicit LSD nowadays ranges from 20 to
80 µg per dose, which is considerably less than doses reported during the 1960s and early
1970s, of 100-200 µg or higher per unit. Experienced users typically administer 100-200
µg for a “good high”. The potency of liquid LSD in dropper bottles may vary because the
liquid is water based.
Route of Administration: Primarily oral administration, but can be inhaled, injected,
and transdermally applied.
Pharmacodynamics: LSD is primarily a non-selective 5-HT agonist. LSD may exert its
hallucinogenic effect by interacting with 5-HT 2A receptors as a partial agonist and
modulating the NMDA receptor-mediated sensory, perceptual, affective and cognitive
processes. LSD mimics 5-HT at 5-HT 1A receptors, producing a marked slowing of the
firing rate of serotonergic neurons.
Pharmacokinetics: LSD has a plasma half-life of 2.5-4 hours. Metabolites of LSD
include N-desmethyl-LSD, hydroxy-LSD, 2-oxo-LSD, and 2-oxo-3-hydroxy-LSD. These
metabolites are all inactive.
Molecular Interactions / Receptor Chemistry: Metabolism via cytochrome P450
isoenzymes has not been described.
Blood to Plasma Concentration Ratio: Data not available.
Interpretation of Blood Concentrations: Threshold toxic dose in humans has been
reported with 100-200 µg with associated blood concentrations of 2-30 ng/mL.
Intravenous doses of 1-2 µg /kg have been associated with blood concentrations of 1-5
- 51 -

ng/mL LSD. Single oral doses of 160 µg resulted in peak plasma concentrations of up to
9 ng/mL LSD.
Interpretation of Urine Test Results: LSD use can typically be detected in urine for
periods of 2-5 days. In a reported case of LSD intoxication, a concentration of 11 ng/mL
of LSD was detected in the urine. In subjects receiving 200-400 µg of LSD,
concentrations in urine ranged from 1-55 ng/mL.
Effects: Effects are unpredictable and will depend on the dose ingested, the user’s
personality and mood, expectations and the surroundings.
Psychological: Hallucinations, increased color perception, altered mental state, thought
disorders, temporary psychosis, delusions, body image changes, and impaired depth, time
and space perceptions. Users may feel several emotions at once or swing rapidly from
one emotion to another. “Bad trips” may consist of severe, terrifying thoughts and
feelings, fear of losing control, and despair.
Physiological: Tachycardia, hypertension, dilated pupils, sweating, loss of appetite,
sleeplessness, dry mouth, tremors, speech difficulties, and piloerection.
Side Effect Profile: Rhabdomyolysis, renal failure, prolonged mania, panic, impairment
in color discrimination, and residual visual effects have been described. LSD users may
manifest relatively long-lasting psychoses, such as schizophrenia or severe depression.
Duration of Effects: Onset of effects is rapid following intravenous administration (10
minutes). Following oral ingestion, onset of the first effects are experienced in 20-30
minutes, peaking at 2-4 hours and gradually diminishing over 6-8 hours. Residual effects
may last longer. Flashbacks may occur suddenly, often without warning, and may occur
within a few days or more than a year after use.
Tolerance, Dependence and Withdrawal Effects: Frequent, repeated doses of LSD are
unusual and therefore tolerance is not commonly seen. Tolerance does develop to the
behavioral effects after 3-4 daily doses, but no withdrawal syndrome has been described.
LSD is not considered an addictive drug since it does not produce compulsive drugseeking
behavior.
Drug Interactions: Cross-tolerance with mescaline and psilocybin has been
demonstrated in animal models. LSD blocks subjective alcohol effects in many subjects.
Possible seizures when concurrently taken with lithium or fluoxetine.
Performance Effects: LSD produces significant psychedelic effects with doses as little
as 25-50 µg. LSD impairs reaction time (auditory and visual), choice reaction time, and
visual acuity for up to 4 hours. Impaired divided attention, ataxia, and grossly distorted
perception have also been reported following LSD use.
Effects on Driving: Epidemiology studies suggest the incidence of LSD in driving
under the influence cases is extremely rare. In Denver, Colorado between Jan 1988 to
June 1990, 242 drivers detained for driving while impaired were evaluated by drug
- 52 -

ecognition examiners; only 1 case of LSD was confirmed following urine toxicology
screens.
DEC Category: Hallucinogen.
DEC Profile: Horizontal gaze nystagmus not present; vertical gaze nystagmus not
present; lack of convergence not present; pupil size dilated; reaction to light normal;
pulse rate elevated; blood pressure elevated; body temperature elevated. Other
characteristic indicators may include extreme changes in behavior and mood, trance-like
state, sweating, body tremors, piloerection, hallucinations, paranoia, and changes in sense
of light, hearing, touch and smell.
Panel’s Assessment of Driving Risks: The use of LSD is not compatible with the skills
required for driving due to its severe psychomotor, cognitive and residual effects.
References and Recommended Reading:
Abraham HD. A chronic impairment of colour vision in users of LSD. Br J Psychiat
1982;140(5):518-20.
Aghajanian GK, Marek GJ. Serotonin and hallucinogens. Neuropsychopharm 1999;21(2
Supp):16S-23S.
Aranov VL, Liang X, Russo A, Wang RY. LSD and DOB: Interaction with 5-HT(2A)
receptors to inhibit NMDA receptor-mediated transmission in the rat prefrontal cortex.
Eur J Neurosci 1999;11(9):3064-72.
Barrett SP, Archambault J, Engelberg JM, Pihl RO. Hallucinogenic drugs attenuate the
subjective response to alcohol in humans. Human Psychopharm 2000;15(7):559-65.
Baselt RC. Drug effects on psychomotor performance. Biomedical Publications, Foster
City, CA; pp 225-226;2001.
Burns M, Page T, Leikin J. Drug information handbook for the criminal justice
professional. Lexi-Comp Inc., Hudson, Ohio, USA;1998.
Kawasaki A, Purvin V. Persistent palinopsia following ingestion of lysergic acid
diethylamide (LSD). Arch Opthalm 1996;114(1):47-50.
Kulig K. LSD. Emerg Med Clin N Am 1990;8(3):551-8.
Lechowicz W. LSD determination using high-performance liquid chromatography with
fluorescence spectroscopy. Z Zaga Nauk Sadow 1999;39:54-64.
Madden JS. LSD and post-hallucinogen perceptual disorder. Addiction 1994;89:762-3.
McCarron MM, Walberg CB, Baselt RC. Confirmation of LSD intoxication by analysis
of serum and urine. J Analyt Tox 1990;14(3):165-7.
Smith DE, Seymour RB. Dream becomes nightmare. Adverse reactions to LSD. J Psych
Drugs 1985;17(4):297-303.
Taunton-Rigby A, Sher SE, Kelley PR. Lysergic acid diethylamide: radioimmunoassay.
Science 1980;181:165-6.
Tomaszewski C, Kirk M, Bingham E, Saltzman B, Cook R, Kulig K. Urine toxicology
screens in drivers suspected of driving while impaired from drugs. J Tox Clin Tox
1996;34(1):37-44.
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Upshall DG, Wailling DG. The determination of LSD in human plasma following oral
administration. Clin Chim Acta 1972;36(1):67-73.
Vardy MM, Kay SR. LSD psychosis or LSD-induced schizophrenia A multimethod
inquiry. Arch Gen Psychiat 1983;40(8):877-83.
Williams RH, Erickson T. Evaluating hallucinogenic or psychedelic drug intoxication in
an emergency setting. Lab Med 2000;31(7):394-401.
- 54 -

Methadone
Methadone hydrochloride is a white crystalline powder or colorless crystals. Available
primarily in tablet or liquid form.
Synonyms: 6-dimethylamino-4.4-diphenyl-3-heptanone; Dolophine® Hydrochloride,
Methadose®, Methadone Hydrochloride Intensol TM .
Source: Methadone is a synthetic narcotic analgesic and is a schedule II controlled
substance. Methadone is available by prescription as oral solutions (1-2 mg/mL strength),
tablets (5-10 mg), dispersible tablets (40 mg), or injectable solutions (10 mg/mL).
Drug Class: Narcotic analgesic.
Medical and Recreational Uses: Methadone is an analgesic prescribed for the relief
of moderate to severe pain, and is used in detoxification treatment of opioid dependence
and maintenance in narcotic addiction. Compared to morphine, methadone has a much
longer duration of action, suppressing opiate withdrawal symptoms and remaining
efficacious for an extended period of time with repeated administration. Recreationally,
methadone is abused for its sedative and analgesic effects.
Potency, Purity and Dose: Available as the racemic mixture, (R)- or l-methadone is
8-50 times more potent than the (S)- or d-isomer. For relief of severe acute pain the usual
adult dose is 2.5-10 mg every 3-4 hours. For methadone maintenance the daily dose is
generally 60-80 mg, but can vary from 30-120 mg. For detoxification treatment an initial
oral dose of 15-20 mg is administered, with an additional dose if withdrawal symptoms
are not suppressed; a stabilizing dose of 40 mg in single or divided dosages is prescribed
for 2-3 weeks, then the dose is gradually decreased. Concurrent use of other prescription
medication is common.
Route of Administration:
subcutaneous injection.
Oral ingestion, intravenous, intramuscular or
Pharmacodynamics: Methadone is a long acting µ opioid receptor agonist with potent
central analgesic, sedative, and antitussive actions. Methadone inhibits ascending pain
pathways, alters perception of and response to pain (dissociative effect), and produces
generalized CNS depression. Respiratory depression also occurs due to complete
blockade of respiratory centers to pCO 2 . (S)-Methadone lacks significant respiratory
depressive action and addiction liability.
Pharmacokinetics: When administered orally, methadone is rapidly absorbed from the
gastrointestinal tract and can be detected in the blood within 30 minutes. Oral
bioavailability varies from 41-99% and plasma protein binding is 60-90%. After repeated
administration there is gradual accumulation in tissues. As for most lipid soluble drugs, a
large between and within subject variability is observed. The half-life of (R,S)-
methadone is 15-60 hours, and 10-40 hours for (R)-methadone. Methadone undergoes
extensive biotransformation in the liver primarily to two inactive metabolites,
- 55 -

2-ethylidene-1.5-dimethyl-3.3diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-
diphenyl-1-pyrroline (EMDP), through N-demethylation and cyclization. These are
eliminated by the kidney and excreted through the bile. In total, nine metabolites have
been identified including two minor active metabolites, methadol and normethadol.
Molecular Interactions / Receptor Chemistry: Methadone is metabolized to EDDP via
the cytochrome P450 CYP3A4 isoform. Potential inhibitors of this isoform could
decrease the rate of methadone elimination if administered concurrently, while potential
inducers could increase the rate of elimination. Methadone itself inhibits cytochrome
P450 2D6 isoform.
Blood to Plasma Concentration Ratio: 0.75 and 0.77 reported.
Interpretation of Blood Concentrations: Methadone can be detected in plasma within
30 minutes following oral ingestion, reaching a peak concentration at ~4 hours. Mean
EDDP concentration are ~15% that of methadone. There is often a large overlap between
reported therapeutic (0.03-0.56 mg/L) and fatal concentrations (0.06-3.1 mg/L). Peak
serum concentrations following a single oral dose of 15 mg were 0.075 mg/L, 0.86 mg/L
for 100 mg, and 0.83 mg/L for 120 mg; all at 4 hours. Chronic oral administration of 100-
200 mg to tolerant subjects produced average peak plasma concentrations of 0.83 mg/L at
4 hours, decreasing to 0.46 mg/L at 24 hours. Peak plasma methadone concentrations of
0.034 mg/L were obtained at 50 minutes following intramuscular injection of 10 mg,
while intravenous administration of 10 mg produced concentrations of 0.096 mg/L at 34
minutes. Concentrations greater than 0.10 mg/L are required for prevention of opiate
withdrawal symptoms. In cancer patients treated for pain relief and sedation, methadone
concentrations were 0.35 ± 0.18 mg/L.
Interpretation of Urine Test Results: The percentage of a dose excreted in the urine as
unchanged methadone and EDDP will vary with the pH of the urine. Urinary excretion of
unchanged parent drug is 5-50% and EDDP 3-25%. It may be possible to use excretion
data to monitor individuals’ compliance in a methadone program after establishing their
intraindividual variation in excretion patterns through long-term monitoring.
Effects:
Psychological: Drowsiness, sedation, dizziness, lightheadedness, mood swings
(euphoria to dysphoria), depressed reflexes, altered sensory perception, stupor, and coma.
Physiological: Strong analgesia, headache, dry mouth, facial flushing, nausea,
constipation, respiratory depression, muscle flaccidity, pupil constriction, and decreased
heart rate.
Duration of Effects: Onset of analgesia occurs 10-20 minutes following parenteral
administration and 30-60 minutes after oral administration. Oral administration results in
a delay in onset, lower peak concentration and longer duration of action. Following single
oral doses effects may last 6-8 hours, increasing to 22-48 hours in cases of chronic
administration.
- 56 -

Side Effect Profile: Sedation, alteration in cognitive and sensory efficiency, respiratory
depression, nausea, vomiting, headache, constipation, urinary retention, sweating, sleep
disorders, and concentration disorders. Infrequent side effects include urticaria,
hypersensitivity reaction, shock, and pulmonary edema. Overdose can include slow,
shallow breathing, respiratory depression, clammy skin, convulsions, extreme
somnolence, apnea, circulatory collapse, cardiac arrest, coma, and possible death.
Tolerance, Dependence and Withdrawal Effects: Upon repeated administration,
tolerance may develop to the nauseant, miotic, sedative, respiratory depressant, and
cardiovascular effects of methadone. Tolerance develops more slowly to methadone than
to morphine in some patients. Methadone can produce physiological and psychological
drug dependence of the morphine type, and has the potential for being abused.
Withdrawal symptoms are similar to those of other opioids but are less severe, slower in
onset, and last longer. Symptoms include watery eyes, runny nose, nausea, loss of
appetite, diarrhea, cramps, muscle aches, dysphoria, restlessness, irritability, anxiety,
pupillary dilation, piloerection, tremors, chills, sweating, increased sensitivity to pain,
insomnia, and tachycardia.
Drug Interactions: There is additive CNS depressive effects with concurrent use of
sedatives, hypnotics, tranquilizers, other narcotic analgesics, tricyclic antidepressants,
alcohol and other CNS depressant drugs, resulting in exaggerated respiratory depression
and sedation. Methadone can potentiate the deleterious effects of alcohol. Pentazocine,
nalbuphine, butorphanol and buprenorphine are partial agonists and will behave as
antagonists in the presence of methadone, resulting in the precipitation of withdrawal
symptoms. Rifampin reduces blood concentrations of methadone and may lead to
withdrawal. Blood levels of desipramine have increased with concurrent methadone
therapy.
Performance Effects: In general, laboratory studies have shown that non-tolerant
individuals receiving single doses of methadone have produced dose-dependent
reductions in reaction time, visual acuity, information processing, and sedation.
Significant psychomotor impairments are seldom evident when tolerant subjects have
been tested, including performance deficits in reaction time, attention, and peripheral
vision. In the majority of experimental clinical trials, psychophysical performance tests
have yielded the same results for methadone substitution patients as for control groups.
However, variable results have been observed. Attention and perception tasks have been
impaired in methadone maintenance patients, but sociodemographic factors may have
played a role. In patients receiving 35-85 mg methadone daily, significant impairment
was measured on attention, perception and learning tasks but there was no reaction time
deficit. In patients receiving a daily average of 63 mg methadone, significant impairment
in distance perception, attention span and time perception was observed. No significant
adverse effects were measured with addicts stabilized for at least 1 year on daily oral
doses of methadone.
Effects on Driving: The drug manufacturer cautions that methadone may impair the
mental and/or physical abilities required for the performance of potentially hazardous
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tasks, and that the sedative effects of the drug may be enhanced by concurrent use of
other CNS depressants, including alcohol. In healthy, non-methadone using volunteers,
single doses of methadone will impair driving ability. Numerous European studies of
long-term methadone maintenance patients have shown that appropriately administered
methadone does not cause significant psychomotor or cognitive impairment when
administered regularly and when the subject abstains from all other drugs. However, in
the majority of cases, patients did not exhibit stable abstinence from drug use and had an
increased occurrence of simultaneous psychiatric/neurotic disorders or personality
disturbances which, by themselves, could be a reason to doubt their driving ability. In
Germany, the Joint Advisory Council for Traffic Medicine at the Federal Ministry of
Transport, Building and Housing and the Federal Ministry for Health issued the
following recommendation: Heroin addicts treated with methadone are generally not fit
to drive; however, these patients may be considered fit to drive if they show a period of
methadone substitution for more than a year; stable psychosocial integration; no evidence
of the consumption of additional psychotropic substances; evidence of a subject’s
readiness to feel responsible for himself/herself; therapy compliance; and no evidence of
serious personality defects.
DEC Category:
Narcotic Analgesic.
DEC Profile: Horizontal gaze nystagmus not present; vertical gaze nystagmus not
present; lack of convergence not present; pupil size constricted; little to no reaction to
light; pulse rate down; blood pressure down; body temperature down. Other characteristic
indicators may include muscle tone flaccidity, droopy eyelids, drowsiness, depressed
reflexes, and dry mouth.
Panel’s Assessment of Driving Risks: Moderate to severely impairing in naïve or nontolerant
individuals, causing dose-dependent reductions in reaction time, visual acuity
and information processing. Significant psychomotor impairment is not expected in
tolerant individuals. Driving ability and driving fitness are nevertheless often limited
because of consumption of additional psychotropic substances and psychopathological
findings.
References and Recommended Reading:
Baselt RC. Drug effects on psychomotor performance. Biomedical Publications, Foster
City, CA; pp 241-243;2001.
Berghaus G, Staak M, Glazinski R, Höher K, Joó S, Friedel B. Complementary empirical
study on the driver fitness of methadone substitution patients. In: Alcohol, Drugs and
Traffic Safety, T92, Verlag TÜV Rheinland GmbH Köln 1993; 120-26.
Chesher GB. Understanding the opioid analgesics and their effect on driving
performance. Alcohol, Drugs & Driving 1989;5:111-38.
Felder C, Uehlinger C, Baumann P, Powell K, Eap CB. Oral and intravenous methadone
use: some clinical and pharmacokinetic aspects. Drug & Alcohol Dependence
1999;55:137-43.
- 58 -

Friedel B, Berghaus G. Methadone and driving. In: Alcohol, Drugs and Traffic Safety
T95. Proceedings of the 13th International Conference on Alcohol, Drugs and Traffic
Safety, Adelaide, August 1995, 307-10.
Gordon AM, Friel P, Logan BK. Methadone findings in drivers and post mortem cases in
Washington state. Presented at the Society of Forensic Toxicologist annual meeting,
New Orleans LA, 2001.
Gordon NB, Appel PW. Functional potential of the methadone-maintained person.
Alcohol, Drugs & Driving 1995;11:31-7.
Hauri-Bionda R, Bar W, Friedrich-Koch A. Driving fitness/driving capacity of patients
treated with methadone. Schweiz Med Wochenschr 1998;128(41):1538-47.
Inturrisi CE, Verebely K. The levels of methadone in plasma in methadone maintenance.
Clin Pharmac Ther 1972;13:633-7.
Joó S. Methadone substitution and driver ability: Research findings and conclusions from
a discussion of experts. J Traffic Med 1994;22:101-3.
Physicians’ Desk Reference, Medical Economics Company, Montvale, NJ, 2002.
- 59 -

- 60 -

Methamphetamine (and Amphetamine)
Methamphetamine hydrochloride is a white to light brown crystalline powder, or clear
chunky crystals resembling ice. Methamphetamine base is a liquid.
Synonyms: Methamphetamine: chalk, chrissy, crank, crystal, glass, go, hydro, ice, meth,
rock candy, speed, whiz; Desoxyn®; Amphetamine: dextroamphetamine; Dexedrine®,
Adderall®, Benzedrine®, DextroStat®, Biphetamine®, Gradumet®.
Source: The majority of street methamphetamine is produced in clandestine laboratories
(e.g. reduction of l-ephedrine or d-pseudoephedrine over red phosphorus with hydroiodic
acid, or reduction with sodium or lithium in condensed liquid ammonia).
Methamphetamine remains concentrated in western U. S. states and some rural areas
elsewhere. d-Methamphetamine is a schedule II controlled substance (Desoxyn®)
available in 5 mg white, 10 mg pink, and 15 mg yellow strength tablets. Amphetamine is
also a Schedule II controlled substance and is usually supplied as the sulfate salt of the d-
isomer (Dexedrine®), or as the racemic mixture (Benzedrine®), or a mixture of the two
(Adderall®). Dexedrine® is available in 5, 10, and 15 mg strength, orange/black
capsules, or 5 mg tablets. Adderall® is available in 5, 7.5, 10, 12.5, 20, and 30 mg
strength, blue or orange tablets.
Drug Class: CNS stimulant, sympathomimetic, appetite suppressant.
Medical and Recreational Uses: Medicinally, methamphetamine is used in the
treatment of narcolepsy, attention deficit disorder (ADD), and attention deficit
hyperactivity disorder (ADHD). Typical doses are 10 mg/day or up to 40 mg daily, and a
course of greater than six weeks is not recommended. Methamphetamine is infrequently
used in the treatment of obesity, overeating disorders, and weight loss due to its abuse
potential. Amphetamine is also used in ADD, narcolepsy, and weight control.
Recreationally, methamphetamine is abused to increase alertness, relieve fatigue, control
weight, treat mild depression, and for its intense euphoric effects.
Potency, Purity and Dose: Purity of methamphetamine is currently very high, at 60-
90%, and is predominantly d-methamphetamine which has greater CNS potency than the
l-isomer or the racemic mixture. Common abused doses are 100-1000 mg/day, and up to
5000 mg/day in chronic binge use. Therapeutic doses of Desoxyn® are 2.5-10 mg daily,
with dosing not exceed 60 mg/day. To treat narcolepsy, 5-60 mg/day of amphetamine is
ingested in divided doses; and in ADD and ADHD doses of 2.5-10 mg/day is
administered, depending on age.
Route of Administration: Methamphetamine users often begin with intranasal or oral
use and progress to intravenous use, and occasionally smoking. In contrast to cocaine, the
hydrochloride salt of methamphetamine can itself be smoked. Methamphetamine is used
sometimes with alcohol or marijuana, particularly during the withdrawal phase.
Pharmacodynamics: Methamphetamine increases synaptic levels of the
neurotransmitters dopamine, serotonin (5-HT) and norepinephrine, and has α and β
- 61 -

adrenergic agonist effects. Norepinephrine is responsible for methamphetamine’s
alerting, anorectic, locomotor and sympathomimetic effects; dopamine stimulates
locomotor effects, psychosis, and perception disturbances; and 5HT is responsible for
delusions and psychosis. Methamphetamine’s effects are similar to cocaine but its onset
is slower and the duration is longer. Racemic amphetamine and d-amphetamine have
similar chemical properties and actions to methamphetamine but are less potent.
Pharmacokinetics: Following oral administration, peak methamphetamine
concentrations are seen in 2.6-3.6 hours and the mean elimination half-life is 10.1 hours
(range 6.4-15 hours). The amphetamine metabolite peaks at 12 hours. Following
intravenous injection, the mean elimination half-life is slightly longer (12.2 hours).
Methamphetamine is metabolized to amphetamine (active), p-OH-amphetamine and
norephedrine (both inactive). Several other drugs are metabolized to amphetamine and
methamphetamine and include benzphetamine, selegeline, and famprofazone.
Molecular Interactions / Receptor Chemistry: Methamphetamine is metabolized to
amphetamine via cytochrome P450 2D6. Potential inhibitors of the 2D6 isoenzyme could
decrease the rate of methamphetamine elimination if administered concurrently, while
potential inducers could increase the rate of elimination.
Blood to Plasma Concentration Ratio: 0.65 (N=1).
Interpretation of Blood Concentrations: Blood concentrations can generally be used to
distinguish therapeutic use from abuse. Concentrations of 0.02-0.05 mg/L are typical for
therapeutic use, and up to 0.2 mg/L have been documented. Concentrations greater than
this represent abuse. Concentrations do not disclose phase of use. Normal concentrations
in recreational use are 0.01 to 2.5 mg/L (median 0.6 mg/L). Concentrations above this
range will likely be associated with severe, possibly life threatening, toxicity. There is no
evidence for improved performance in any task or test following use of doses greater than
40 mg (or concentrations greater than 0.2 mg/L).
Peak blood methamphetamine concentrations occur shortly after injection, a few
minutes after smoking, and around 3 hours after oral dosing. Peak plasma amphetamine
concentrations occur around 10 hours after methamphetamine use.
Interpretation of Urine Test Results: Positive results generally indicate use within 1-4
days but could be up to a week following heavy chronic use. Rate of excretion into the
urine is heavily influenced by urinary pH. Between 30-54% of an oral dose is excreted in
urine as unchanged methamphetamine and 10-23% as unchanged amphetamine.
Following an intravenous dose, 45% is excreted as unchanged parent drug and 7%
amphetamine.
Effects: Methamphetamine effects are less intense after oral ingestion than following
smoked or intravenous use.
Early phase – Psychological: Euphoria, excitation, exhilaration, rapid flight of ideas,
increased libido, rapid speech, motor restlessness, hallucinations, delusions, psychosis,
insomnia, reduced fatigue or drowsiness, increased alertness, heightened sense of well
- 62 -

eing, stereotypes behavior, feelings of increased physical strength, and poor impulse
control.
Early phase – Physiological: Increased heart rate, increased blood pressure, increased
respiration rate, elevated temperature, palpitations, irregular heartbeat, dry mouth,
abdominal cramps, appetite suppressed, twitching, pallor, dilated pupils, HGN at high
doses, faster reaction time, increased strength, and more efficient glucose utilization.
Late phase – Psychological: Dysphoria, residual stimulation, restlessness, agitation,
nervousness, paranoia, violence, aggression, lack of coordination, pseudo-hallucinations,
delusions, psychosis, and drug craving.
Late phase – Physiological: Fatigue, sleepiness with sudden starts,
itching/picking/scratching, normal heart rate, and normal to small pupils which are
reactive to light.
Binge use of methamphetamine can be broken down into the following phases:
Rush – (5 minutes) intense euphoria, rapid flight of ideas, sexual stimulation, high
energy, obsessive/compulsive activity, thought blending, dilated pupils; Shoulder –
(1 hour) less intense euphoria, hyperactivity, rapid flight of ideas, obsessive/compulsive
activity, thought blending, dilated pupils; Binge use – (1-5 days) the drug is frequently
readministered in an attempt to regain or maintain euphoria; Tweaking – (4-24 hours)
dysphoria, scattered and disorganized thought, intense craving, paranoia, anxiety and
irritability, hypervigilance, auditory and tactile hallucinations, delusions, and normal
pupils; Crash – (1-3 days) intense fatigue, uncontrollable sleepiness and catnapping,
continuing stimulation, drug craving; Normal – (2-7 days) apparent return to “normalcy”
although drug craving may appear; Withdrawal – anergia, anhedonia, waves of intense
craving, depression, hypersomnolence, exhaustion, extreme fatigue.
Side Effect Profile: Light sensitivity, irritability, insomnia, nervousness, headache,
tremors, anxiety, suspiciousness, paranoia, aggressiveness, delusions, hallucinations,
irrational behavior, and violence. In overdose, symptoms may include hyperthermia,
tachycardia, severe hypertension, convulsions, chest pains, stroke, cardiovascular
collapse, and possible death. Other common side effects following abuse of
amphetamines include viral hepatitis, Sexually Transmitted Diseases (STDs), HIV,
septicemia, abscesses, collapsed blood vessels, and malnutrition. Chronic abuse generally
produces a psychosis that resembles schizophrenia and is characterized by paranoia,
picking at the skin, preoccupation with one’s own thoughts, and auditory and visual
hallucinations. Violent and erratic behavior is frequently seen among chronic abusers.
Over time, methamphetamine appears to cause reduced levels of dopamine, which can
result in symptoms like those of Parkinson’s disease.
Duration of Effects: Onset of effects is rapid following intravenous use and smoking,
while effects onset more slowly following oral use. Overall effects typically last 4-8
hours; residual effects can last up to 12 hours.
Tolerance, Dependence and Withdrawal Effect: Methamphetamine has a high potential
for abuse and dependence. Tolerance may develop and users may quickly become
addicted and use it with increasing frequency and in increasing doses. Abrupt
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discontinuation of use can produce extreme fatigue, mental depression, apathy, long
periods of sleep, irritability, and disorientation.
Drug Interactions: Phenobarbital, propoxyphene, phenytoin and MAOI’s slow the
metabolism of amphetamines and increases their effect on the release of norepinephrine
and other monoamines from adrenergic nerve endings. Amphetamines may counteract
sedative effects of antihistamines. Methamphetamine may restore ethanol induced
impairment in simple repetitive tasks of short duration, however, there is no restoration of
ethanol-induced deficits of balance and steadiness. In general, high doses of
amphetamines are likely to increase the impairing effects of alcohol. Chlorpromazine and
haloperidol block dopamine and norepinephrine reuptake, thus inhibiting the central
stimulant effects of amphetamines. Amphetamine potentiates the analgesic effect of
meperidine.
Performance Effects: Laboratory studies have been limited to much lower doses than
those used by methamphetamine abusers. Doses of 10-30 mg methamphetamine have
shown to improve reaction time, relief fatigue, improve cognitive function testing,
increase subjective feelings of alertness, increase time estimation, and increase euphoria.
However, subjects were willing to make more high-risk choices. The majority of
laboratory tests were administered 1 hour post dose. Expected performance effects
following higher doses may include agitation, inability to focus attention on divided
attention tasks, inattention, restlessness, motor excitation, increased reaction time, and
time distortion, depressed reflexes, poor balance and coordination, and inability to follow
directions.
Effects on Driving: The drug manufacturer states that patients should be informed that
methamphetamine and amphetamine may impair the ability to engage in potentially
hazardous activities such as driving a motor vehicle. In epidemiology studies drive-offthe-road
type accidents, high speed, failing to stop, diminished divided attention,
inattentive driving, impatience, and high risk driving have been reported. Significant
impairment of driving performance would also be expected during drug withdrawal. In a
recent review of 101 driving under the influence cases, where methamphetamine was the
only drug detected, blood concentrations ranged from

characteristic indicators may include restlessness, body tremors, talkativeness,
exaggerated reflexes, anxiety, and track marks or recent injection sites.
Panel’s Assessment of Driving Risks: At lower dose, amphetamines have few effects on
cognitive functioning and may result in an enhancement of some psychomotor tasks, but
risk-taking increases at higher doses and responses become inappropriate. Drug
withdrawal could also lead to the impairment of psychomotor skills required for safe
driving.
References and Recommended Reading:
Baselt RC. Drug effects on psychomotor performance. Biomedical Publications, Foster
City, CA; pp 30-5, pp 244-6;2001.
Forney R. Stimulants, drugs & driving, NIDA research monograph 11, ed by Willette, RE
1977:73-6.
Gygi MP, Gygi SP, Johnson M, Wilkins DG, Gibb JW, Hanson GR. Mechanisms for
tolerance to methamphetamine effects. Neuropharmacol 1996;35(6):751-7.
Hurst PM. Amphetamines and driving. Alc Drugs Driv 1987;3(1):13-6.
Jerome L, Segal A. Benefit of long-term stimulus on driving in adults with ADHD. J
Nerv Ment Dis 2001(1);189:63-4.
Logan BK. Amphetamines: an update on forensic issues. J Anal Toxicol 2001;25(5):400-
4.
Logan BK. Methamphetamine and driving impairment. J Forensic Sci 1996;41(3):457-
64.
Logan BK. Methamphetamine - Effects on Human Performance and Behavior. Forens
Sci Rev 2002;14(1/2):133-51.
National Transportation Safety Board safety study: Fatigue, alcohol, other drugs, and
medical factors in fatal-to-the-driver heavy truck crashes (vol I and II). Accession#
PB90-917002, report# NTSB/SS-90/01/02, National Transportation Safety Board,
Washington DC, 1990.
Perez-Reyes M, White WR, McDonald SA, Hicks RE, Jeffcoat AR, Hill JM, Cook CE.
Clinical effects of daily methamphetamine administration. Clin Neuropharm
1991(4);14:352-8.
Physicians’ Desk Reference, Medical Economics Company, Montvale, NJ, 2002.
Smith DE, Fischer CM. An nalysis of 310 cases of acute high dose methamphetamine
toxicity in Haight-Ashbury. Clin Toxicol 1970;3(1):117-24.
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- 66 -

Methylenedioxymethamphetamine (MDMA, Ecstasy)
MDMA is a white, tan or brown powder. Available primarily in tablet form.
Synonyms: 3,4-methylenedioxymethamphetamine; ecstasy, ADAM, candy canes, disco
biscuit, doves, E, eckie, essence, hug drug, love drug, M&M, rolls, white doves, X, XTC.
Source: MDMA is the methylenedioxy derivative of methamphetamine. Starting
materials in its illicit manufacture include isosafrole (Leuckart reaction) and safrole
(Merck patent). MDMA is most commonly found in tablet forms of various colors,
carrying distinctive markings on one side such as a dove, E, yin/yang symbol, Mitsubishi
symbol, etc. MDMA is a Schedule I controlled substance.
Drug Class: Mild CNS stimulant, empathogen, entactogen, mild hallucinogen and
psychedelic, appetite suppressant.
Medical and Recreational Uses: Originally patented as an appetite suppressant and used
as a possible adjunct to psychotherapy, there is currently no legitimate medical use in the
U. S. MDMA is recreationally used as a party, rave or dance drug for its stimulant, mild
hallucinogenic, and empathogenic properties.
Potency, Purity and Dose: MDMA exists as a racemic mixture, with the S-(+)-
enantiomer having greater CNS potency compared to the R-(-)-enantiomer. Potency of
street samples is highly variable, and tablets sold as ‘ecstasy’ may in fact contain little or
no MDMA, but may contain caffeine, ephedrine, phenylpropanolamine,
paramethoxyamphetamine (PMA), methylenedioxyamphetamine (MDA),
dextromethorphan, amphetamine, methamphetamine, and ketamine. Some tablets have
been reported to contain LSD or heroin. Typical doses in a series of pills can range
between 10–150 mg of MDMA. User surveys report a range of doses between 50-700 mg
in a session, with an average of 120 mg. Most common pattern of use is binge
consumption at all night rave or dance parties. MDMA is frequently taken with other
recreational drugs such as ethanol, marijuana, cocaine, methamphetamine, nitrous oxide,
and GHB.
Route of Administration: Primarily oral administration, although MDMA could
conceivably be dissolved and injected, or crushed and snorted.
Pharmacodynamics: MDMA is a phenylethylamine that has stimulant as well as
psychedelic effects. MDMA is related in structure and effects to methamphetamine,
however, it has significantly less CNS stimulant properties than methamphetamine.
MDMA has a high affinity for 5-HT 2 receptors. Both S- and R- enantiomers of MDMA
cause acute depletion of presynaptic serotonin (5-HT), depression of 5-HT synthesis by
tryptophan hydroxylase, and retrograde destruction of 5-HT neurons following high
doses. MDMA also increases levels of norepinephrine and dopamine. The MDMA
metabolite, S-(+)- MDA, elicits more stereotypic behavior and is an even more potent
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neurotoxin than the parent drug. MDA destroys serotonin-producing neurons which play
a direct role in regulating aggression, mood, sexual activity, sleep, and sensitivity to pain.
Pharmacokinetics: MDMA is rapidly absorbed and the half-life of MDMA is ~ 7 hours,
although non-linear pharmacokinetics have been observed due to stereoselective
pharmacokinetics of the enantiomers. MDMA is metabolized to MDA which is the only
metabolite reported in blood and plasma. S-(+)- MDA accumulates in blood due to
stereoselective metabolism of S-(+)-MDMA. MDA is further metabolized to its 3-
hydroxy-4-methoxy and 3,4-dihydroxy derivatives (HMA and HHA). Additional
MDMA metabolites include 3-hydroxy-4-methoxymethamphetamine (HMMA) and 3,4-
dihydroxymethamphetamine (HHMA). These polar hydroxylated metabolites are
conjugated prior to their excretion in urine.
Molecular Interaction / Receptor Chemistry: The majority of MDMA N-demethylation
to MDA is via the cytochrome P450 2D6 isoenzyme, with minor contributions by the
1A2 isoform. Potential inhibitors of these isoenzymes could decrease the rate of MDMA
elimination if administered concurrently, while potential inducers could increase the rate
of elimination. Both extensive and poor MDMA metabolizers have been identified.
Blood to Plasma Concentration Ratio: Data not available.
Interpretation of Blood Concentrations: No clear correlation exists between MDMA
blood concentrations and effects. MDMA and MDA are the analytes detected in blood,
with MDA concentrations typically only 5-10% of the corresponding MDMA
concentrations. Higher MDA:MDMA ratios may indicate co-administration of MDA.
Plasma concentrations following single oral doses of 50, 75, 100, 125 and 150 mg of
MDMA were 0.02-0.08 mg/L, 0.13 mg/L, 0.19-0.21 mg/L, 0.24 mg/L, and 0.44 mg/L,
respectively. Peak concentrations of MDMA and MDA are observed at 1.5-2 hours and 4
hours, respectively.
Interpretation of Urine Test Results: MDMA, MDA, HMMA, HHMA, HMA and
HHA are typically found in urine following their hydrolysis. MDA and HMMA
concentrations in urine are typically 10-15% of the corresponding MDMA
concentrations.
Effects:
Psychological: Low to moderate doses (50-200 mg) produce mild intoxication,
relaxation, euphoria, an excited calm or peace, feelings of well-being, increase in
physical and emotional energy, increased sociability and closeness, heightened
sensitivity, increased responsiveness to touch, changes in perception, and empathy. At
higher doses, agitation, panic attacks, and illusory or hallucinatory experiences may
occur.
Physiological: Low to moderate doses (50-200 mg) produce mild visual disturbances
(blurred or double vision, increased light sensitivity), dilated pupils, dry mouth, sweating,
ataxia, muscle tension, and involuntary jaw clenching.
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Side Effect Profile: Impairment of cognitive, perception, and mental associations.
Psychological difficulties include confusion, depression, sleep problems, drug craving,
severe anxiety, and paranoia. Subjects may experience fatigue, uncoordinated gait,
decreased fine motor skills, attentional dysfunction (difficulty to maintain attention
during complex tasks), preoccupation, hyperthermia, tachycardia, hyperthermia,
hyponatremia, convulsions, and catatonic stupor. Prolonged cognitive and behavioral
effects may occur including poor memory recall, flashbacks, panic attacks, psychosis,
and depersonalization due to serotonergic neuron damage and decreased serotonin
production as a result of long-term use.
Duration of Effects: Following oral administration, effects onset in 20-30 minutes and
desired effects may last only an hour or more, depending on dose. Other general effects
last for approximately 2-3 hours. LSD is sometimes used in combination with MDMA to
increase its duration of effects. Residual and unwanted effects are generally gone within
24 hours although confusion, depression and anxiety may last several weeks.
Tolerance, Dependence and Withdrawal Effect: Drug stacking refers to the ingestion
of single doses consecutively as effects begin to wane, similar to cocaine or
methamphetamine binges. Such extensive or binge use usually occurs over weekends,
and can result in exhaustion, apathy, depression, irritability, insomnia and muscle tension
early the next week (often referred to as “terrible Tuesdays”). Tolerance does develop,
however, the occurrence of physical and/or psychological dependence is unknown.
Persistent neurological deficits may occur, including serotonergic neuron damage which
leads to less production of serotonin.
Drug Interactions: The dopamine D 2 receptor antagonist, haloperidol, attenuates
psychological effects of MDMA but has no effect on physiological effects.
Performance Effects: MDMA can enhance impulsivity and make it difficult for a
person to maintain attention during complex tasks (selective attention, divided and
sustained attention, and complex attention tasks). Laboratory studies have demonstrated
changes in cognitive, perception and mental associations, instability, uncoordinated gait,
and poor memory recall. Distortion of perception, thinking, and memory, impaired
tracking ability, disorientation to time and place, and slow reactions are also known
performance effects. Single oral doses of MDMA causes subjective excitability, anxiety,
perceptual changes, and thought disorders 1-3 hours post dose.
Effects on Driving: In an advanced driving simulator study, subjects were given a
mean single dose of 56 mg MDMA. Compared to a sober state, moderate effects on
vehicle control, acceptance of higher levels of risk, acute changes in cognitive
performance, and impaired information processing ability were observed. In six subjects
arrested for driving under the influence, MDMA was the only drug detected at blood
concentrations ranging from

MDMA concentrations ranging from 0.001-0.514 mg/L (mean 0.076 mg/L) in 18 cases
of driving impairment; blood MDMA concentrations ranging from 0.04-0.38 mg/L (mean
0.18±0.14 mg/L; median 0.19 mg/L) in 9 impaired driving cases; blood MDMA
concentrations of 0.12, 0.08, and 0.14 mg/L in 3 impaired driving cases; and a blood
MDMA concentration of 2.14 mg/L and urine 118.8 mg/L in one driving fatality case.
Another study reported the occurrence of speeding, jumping red lights,
hallucinations/delusions, and a sense of detachment in five impaired driving cases,
however, no MDMA concentrations were mentioned.
DEC Category: Hallucinogen; (with many characteristics similar to a CNS stimulant)
DEC Profile: Horizontal gaze nystagmus not present; vertical gaze nystagmus not
present; lack of convergence not present; pupil size dilated; reaction to light slow; pulse
rate elevated; blood pressure normal to elevated; body temperature normal to elevated.
Other characteristic indicators may include profuse sweating, muscle twitching, body
tremors, and poor performance in field sobriety tests. Subjects are usually described as
very cooperative and “laid-back”. Note that elevated blood pressure and body
temperature are not always observed.
Panel’s Assessment of Driving Risks: Low to moderate single doses of MDMA can
cause acute changes in cognitive performance and impair information processing, which
in turn would impair driving ability. Basic vehicle control is only moderately affected,
however, subjects may accept higher levels of risk.
References and Recommended Reading:
Baselt RC. Drug effects on psychomotor performance. Biomedical Publications, Foster
City, CA; pp 255-256;2001.
Brookhuis KA, DeWaard D, Pernot LMC. A driving simulator study on driving
performance and traffic safety after multiple drug use, consisting of MDMA (Ecstasy)
and various other psychoactive compounds. Proceedings of the International Council
on Alcohol Drugs and Traffic Safety (ICADTS), Stockholm Sweden, May 2000.
Climko RP, Roehrich H, Sweeney DR, Al-Razi J. Ecstasy: a review of MDMA and
MDA. Intl J Psychiatry Med 1986-87;16(4):359-72.
Crifasi J, Long C. Traffic fatality related to the use of methylenedioxymethamphetamine.
J Forens Sci 1996;41(6):1082-4.
Davies JP, Evans RON, Newington DP. Ecstasy related trauma. J Accid Emerg Med
1998;15(6):436.
de la Torre R, Farre M, Ortuno J, Mas M, Brenneissen R, Roset PN, Segura J, Cami J.
Non-linear pharmacokinetics of MDMA (‘ecstasy’) in humans. Br J Clin Pharmacol
2000;49(2):104-9.
de Waard D, Brookhuis KA, Pernot LMC. A driving simulator study of the effects of
MDMA (Ecstasy) on driving performance and traffic safety. Proceedings of the
International Council on Alcohol Drugs and Traffic Safety (ICADTS), Stockholm
Sweden, May 2000.
Downing J. The psychological and physiological effects of MDMA on normal
volunteers. J Psychoactive Drugs 1986;18(4):335-40.
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Gouzoulis-Mayfrank E, Daumann J, Tuchtenhagen F, Pelz S, Becker S, Kunert H-J,
Fimm B, Sass H. Impaired cognitive performance in drug free users of recreational
ecstasy (MDMA). J Neurol Neurosurg Psychiatry 2000;68(16):719-25.
Jacobs MR (ed). MDMA (“Ecstasy”; 3,4-methylenedioxymethamphetamine). In: Drugs
and Drug Abuse. 2 nd edition. Addiction Research Foundation. Toronto, Canada
1987:337-43.
Logan BK, Couper FJ. 3,4-methoxymethamphetamine (MDMA, Ecstasy) and driving
impairment. J Forens Sci 2001;46(6):154-61.
McCann UD, Mertl M, Eligulashvili V, Ricuarte GA. Cognitive performance in (+/-) 3,4-
methylenedioxymethamphetamine (MDMA, “ecstasy”) users: a controlled study.
Psychopharmacology 1999;143(4):417-25.
McGuire P. Long term psychiatric and cognitive effects of MDMA use. Toxicol Lett
2000;112-113:153-6.
Moeller MR, Hartung M. Ecstasy and related substances – serum levels in impaired
drivers. J Anal Toxicol 1997;21(7):591.
Morgan MJ. Recreational use of “ecstasy” (MDMA) is associated with elevated
impulsivity. Neuropsychopharm 1998;19(4):252-64.
Morland J. Toxicity of drug abuse – amphetamine designer drugs (ecstasy): mental
effects and consequences of single dose use. Toxicol Lett 2000;112-113:147-52.
Omtzigt JGC, Vermasse CJ, Zweipfenning PGM. Deaths associated with amphetamine,
3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyethamphetamine
(MDEA), or 3,4-methylenedioxyamphetamine (MDA) abuse. Proceedings of the 23 rd
meeting of the International Association of Forensic Toxicologists (TIAFT), Tampa,
FL 1994.
Parrott AC, Lasky J. Ecstasy (MDMA) effects upon mood and cognition: before, during
and after a Saturday night dance. Psychopharmacology 1998;139(3):261-8.
Schifano F. Dangerous driving and MDMA ("Ecstasy") abuse. J Serotonin Research
1995;1:53-7.
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Morphine (and Heroin)
Morphine and heroin are white, crystalline powders. Illicit heroin may vary in color from
white to dark brown due to impurities, or may appear as a black tar-like material.
Synonyms: Morphine: Astramorph®, Duramorph®, Infumorph®, Kadian®, Morphine
Sulfate®, MSIR®, MS-Contin®, Oramorph SR®, Roxanol®. Heroin: diacetylmorphine,
diamorphine; Mexican brown or Mexican black tar heroin; bags, blue-steel, China white,
H, horse, junk, no-name, silk, skag, smack. Scramble (cut heroin), bone (uncut heroin for
smoking), chippers (occasional users).
Source: Morphine is a naturally occurring substance extracted from the seedpod of the
poppy plant, Papavar somniferum. The milky resin that seeps from incisions made in the
unripe seedpod is dried and powdered to make opium, which contains a number of
alkaloids including morphine. Morphine concentration in opium can range from 4-21%.
An alternate method of harvesting morphine is by the industrial poppy straw process of
extracting alkaloids from the mature dried plant, which produces a fine brownish powder.
Morphine is a schedule II controlled substance and is available in a variety of prescription
forms: injectables (0.5-25 mg/mL strength); oral solutions (2-20 mg/mL); immediate and
controlled release tablets and capsules (15-200 mg); and suppositories (5-30 mg). Heroin
is a schedule I controlled substance and is produced from morphine by acetylation at the
3 and 6 positions. The majority of heroin sold in the U. S. originates from Southeast Asia,
South America (Columbia) and Mexico. Low purity Mexican black tar heroin is most
common on the West coast, while high purity Columbian heroin dominates in the East
and most mid-western states.
Drug Class: Narcotic analgesic.
Medical and Recreational Uses: Morphine is used medicinally for the relief of
moderate to severe pain in both acute and chronic management. It can also be used to
sedate a patient pre-operatively and to facilitate the induction of anesthesia. Heroin has
no currently accepted medical uses in the U.S., however, it is an analgesic and
antitussive.
Potency, Purity and Dose: The dosage of morphine is patient-dependent. A usual
adult oral dose of morphine is 60-120 mg daily in divided doses, or up to 400 mg daily in
opioid tolerant patients. Recreationally, daily heroin doses of 5-1500 mg have been
reported, with an average daily dose of 300-500 mg. Addicts may inject heroin 2-4 times
per day. Depending on the demographic region, the street purity of heroin can range from
11-72% (average U.S. purity is ~38%). Heroin may be cut with inert or toxic adulterants
such as sugars, starch, powdered milk, quinine, and ketamine. Heroin is often mixed with
methamphetamine or cocaine (“speedball”) and injected; or co-administered with
alprazolam, MDMA (Ecstasy), crack cocaine, or diphenhydramine.
Route of Administration: Morphine: oral, intramuscular, intravenous, rectal, epidural,
and intrathecal administration. Morphine tablets may be crushed and injected, while
opium can be smoked. Heroin: smoked, snorted, intravenous (“mainlining”), and
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subcutaneous (“skin popping”) administration. Black tar heroin is typically dissolved,
diluted and injected, while higher purity heroin is often snorted or smoked.
Pharmacodynamics: Morphine produces its major effects on the CNS primarily through
µ-receptors, and also at κ- and δ-receptors. µ 1 -receptors are involved in pain modulation,
analgesia, respiratory depression, miosis, euphoria, and decreased gastrointestinal
activity; µ 2 -receptors are involved in respiratory depression, drowsiness, nausea, and
mental clouding; κ-receptors are involved in analgesia, diuresis, sedation, dysphoria, mild
respiratory depression, and miosis; and δ-receptors are involved in analgesia, dysphoria,
delusions, and hallucinations. Heroin has little affinity for opiate receptors and most of its
pharmacology resides in its metabolism to active metabolites, namely 6-acetylmorphine,
morphine, and morphine-6-glucuronide.
Pharmacokinetics: The oral bioavailability of morphine is 20-40%, and 35% is bound
in plasma. Morphine has a short half-life of 1.5 - 7 hours and is primarily
glucuroconjugated at positions 3 and 6, to morphine-3-glucuronide (M3G) and morphine-
6-glucuronide (M6G), respectively. A small amount (5%) is demethylated to
normorphine. M6G is an active metabolite with a higher potency than morphine, and can
accumulate following chronic administration or in renally impaired individuals. The halflife
of M6G is 4 +/- 1.5 hours. Close to 90% of a single morphine dose is eliminated in
the 72 hours urine, with 75% present as M3G and less than 10% as unchanged morphine.
Heroin has an extremely rapid half-life of 2-6 minutes, and is metabolized to
6-acetylmorphine and morphine. The half-life of 6-acetylmorphine is 6-25 minutes. Both
heroin and 6-acetylmorphine are more lipid soluble than morphine and enter the brain
more readily.
Molecular Interactions / Receptor Chemistry: The uridine 5’-diphosphateglucuronosyltransferase
(UGT) 2B7 isoform is primarily involved in the metabolism of
morphine. Potential inhibitors of this UGT isoform could decrease the rate of morphine
elimination if administered concurrently, while potential inducers could increase the rate
of elimination.
Blood to Plasma Concentration Ratio: Morphine 1.02; M6G 0.57; M3G 0.59
Interpretation of Blood Concentrations: Tolerance makes interpretation of blood or
plasma morphine concentrations extremely difficult. Peak plasma morphine
concentrations occur within an hour of oral administration, and within 5 minutes
following intravenous injection. Average plasma concentrations of 0.065 mg/L are
necessary for adequate therapeutic analgesia in ambulatory patients. Anesthetic
concentrations can reach beyond 2 mg/L in surgical patients. Following oral doses of 10-
80 mg, corresponding peak morphine concentrations in serum were 0.05-0.26 mg/L.
Following an intravenous dose of 8.75g/70 kg, a peak serum concentration of 0.44 mg/L
was reached. In 10 intravenous drug fatalities, where morphine was the only drug
detected, postmortem whole blood morphine concentrations averaged 0.70 mg/L (range
0.20-2.3 mg/L). Following a single 12 mg intravenous mg dose of heroin, a peak heroin
concentration of 0.141 mg/L was obtained at 2 minutes, while the 6-acetylmorphine and
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morphine concentrations were 0.151 and 0.044, respectively. A single 5 mg intravenous
dose of heroin produced a peak plasma morphine concentration of 0.035 mg/L at 25
minutes, while intravenous doses of 150-200 mg have produced plasma morphine
concentrations of up to 0.3 mg/L. Intranasal administration of 12 mg heroin in 6 subjects
produced average peak concentrations of 0.016 mg/L heroin in plasma within 5 minutes;
0.014 mg/L of 6-acetylmorphine at 0.08-0.17 hours; and 0.019 mg/L of morphine at 0.08-
1.5 hours.
Interpretation of Urine Test Results: Positive morphine urine results generally indicate
use within the last two to three days, or longer after prolonged use. Detection of 6-
acetylmorphine in the urine is indicative of heroin use. High concentrations may indicate
chronic use of the drug. It is important to hydrolyze urine specimens to assess a urine
morphine concentration.
Effects: Depends heavily on the dose of morphine or heroin, the route of administration,
and previous exposure. Following an intravenous dose of heroin, the user generally feels
an intense surge of euphoria (“rush”) accompanied by a warm flushing of the skin, dry
mouth, and heavy extremities. The user then alternates between a wakeful and drowsy
state (“on the nod”).
Psychological: Euphoria, feeling of well-being, relaxation, drowsiness, sedation,
lethargy, disconnectedness, self-absorption, mental clouding, and delirium.
Physiological: Analgesia, depressed heart rate, respiratory depression, CNS depression,
nausea and vomiting, reduced gastrointestinal motility, constipation, flushing of face and
neck due to dilatation of subcutaneous blood vessels, cramping, sweating, pupils fixed
and constricted, diminished reflexes, and depressed consciousness.
Side Effect Profile: Drowsiness, inability to concentrate, apathy, lessened physical
activity, constipation, urinary retention, nausea, vomiting, tremors, itching, bradycardia,
severe respiratory depression, and pulmonary complications such as pneumonia. Medical
complications among abusers arise primarily from adulterants found in street drugs and in
non-sterile injecting practices, and may include skin, lung and brain abscesses, collapsed
veins, endocarditis, hepatitis and HIV/AIDS. Overdose can include slow, shallow
breathing, clammy skin, convulsions, extreme somnolence, severe respiratory depression,
apnea, circulatory collapse, cardiac arrest, coma, and death.
Duration of Effects: Depending on the morphine dose and the route of administration,
onset of effects is within 15-60 minutes and effects may last 4-6 hours. The duration of
analgesia increases progressively with age although the degree of analgesia remains
unchanged. Following heroin use, the intense euphoria lasts from 45 seconds to several
minutes, peak effects last 1-2 hours, and the overall effects wear off in 3-5 hours,
depending on dose.
Tolerance, Dependence and Withdrawal Effects: Both morphine and heroin have high
physical and psychological dependence. With regular use, tolerance develops early to the
duration and intensity of euphoria and analgesia. Withdrawal symptoms may occur if use
is abruptly stopped or reduced. Withdrawal can begin within 6-12 hours after the last
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dose and may last 5-10 days. Early symptoms include watery eyes, runny nose, yawning
and sweating. Major withdrawal symptoms peak between 48-72 hours after the last dose
and include drug craving, restlessness, irritability, dysphoria, loss of appetite, tremors,
severe sneezing, diarrhea, nausea and vomiting, elevated heart rate and blood pressure,
chills alternating with flushing and excessive sweating, goose-flesh, abdominal cramps,
body aches, muscle and bone pain, muscle spasms, insomnia, and severe depression.
Drug Interactions: Alcohol increases the CNS effects of morphine such as sedation,
drowsiness, and decreased motor skills. There is a higher risk of respiratory depression,
hypotension and profound sedation or coma with concurrent treatment or use of other
CNS depressant drugs such as barbiturates, benzodiazepines, hypnotics, tricyclic
antidepressants, general anesthetics, MAO inhibitors, and antihistamines. Morphine may
enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an
increased degree of respiratory depression. Small doses of amphetamine substantially
increase the analgesia and euphoriant effects of morphine and may decrease its sedative
effects. Antidepressants may enhance morphine’s analgesia. Partial agonists such as
buprenorphine, nalbuphine, butorphanol, and pentazocine will precipitate morphine
withdrawal.
Performance Effects: Laboratory studies have shown that morphine may cause sedation
and significant psychomotor impairment for up to 4 hours following a single dose in
normal individuals. Early effects may include slowed reaction time, depressed
consciousness, sleepiness, and poor performance on divided attention and psychomotor
tasks. Late effects may include inattentiveness, slowed reaction time, greater error rate in
tests, poor concentration, distractibility, fatigue, and poor performance in psychomotor
tests. Subjective feelings of sedation, sluggishness, fatigue, intoxication, and body sway
have also been reported. Significant tolerance may develop making effects less
pronounced in long-term users for the same dose. In a laboratory setting, heroin produced
subjective feelings of sedation for up to 5-6 hours and slowed reaction times up to 4
hours, in former narcotic addicts. Euphoria and elation could also play a role on
perception of risks and alteration of behaviors.
Effects on Driving: The drug manufacturer states that morphine may impair the mental
and/or physical abilities needed to perform potentially hazardous activities such as
driving a car, and patients must be cautioned accordingly. Driving ability in cancer
patients receiving long-term morphine analgesia (mean 209 mg daily) was considered not
to be impaired by the sedative effects of morphine to an extent that accidents might
occur. There were no significant differences between the morphine treated cancer patients
and a control group in vigilance, concentration, motor reactions, or divided attention. A
small but significant slowing of reaction time was observed at 3 hours. In several driving
under the influence case reports, where the subjects tested positive for morphine and/or 6-
acetylmorphine, observations included slow driving, weaving, poor vehicle control, poor
coordination, slow response to stimuli, delayed reactions, difficultly in following
instructions, and falling asleep at the wheel.
DEC Category: Narcotic Analgesic.
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DEC Profile: Horizontal gaze nystagmus not present; vertical gaze nystagmus not
present; lack of convergence not present; pupil size constricted; little or no reaction to
light; pulse rate down; blood pressure down; body temperature down. Other characteristic
indicators may include presence of fresh injection marks, track marks, flaccid muscle
tone, droopy eyelids, drowsiness or “on-the-nod”, and low raspy slow speech.
Panel’s Assessment of Driving Risks: Classification of risk depends on tolerance, dose,
time of exposure, acute or chronic use, presence or absence of underlying pain,
physiological status of individual, and the presence of other drugs. Moderately to
severely impairing in non-tolerant individuals. Mild to moderately impairing if morphine
is used as medication on a regular basis for chronic pain. Severely impairing in acute
situations if used orally, or as an intravenous medication, or if either drug is taken
illicitly.
References and Recommended Reading:
Baselt RC. Drug effects on psychomotor performance. Biomedical Publications, Foster
City, CA; pp 186-8, pp 277-81; 2001.
Clemons M, Regnard C, Appleton T. Alertness, cognition and morphine in patients with
advanced cancer. Cancer Treat Rev 1996;22(6):451-68.
Community Epidemiology Working Group, National Institute on Drug Abuse.
Epidemiological trends in drug abuse; Proceedings of the Community Epidemiology
Working Group, Vol 1;June 2000.
Cone E J, Holicky BA, Grant TM, Darwin WD, Goldberger BA. Pharmacokinetics and
pharmacodynamics of intranasal "snorted" heroin. J Anal Toxic 1993;17(6):327-37.
Galski T, Williams JB, Ehle HT. Effects of opioids on driving ability. Eur Respir J
2000;15(3):590-5.
Gjerde H, Morland J. A case of high opiate tolerance: implications for drug analyses and
interpretations. Addict Behav 1991;16(6):507-16.
Hanks GW, O'Neill WM, Simpson P, Wesnes K. The cognitive and psychomotor effects
of opioid analgesics. II. A randomized controlled trial of single doses of morphine,
lorazepam and placebo in healthy subjects. Eur J Clin Pharmacol 1995;48(6):455-60.
Kerr B, Hill H, Coda B, Calogero M, Chapman CR, Hunt E, Buffington V, Mackie A.
Concentration-related effects of morphine on cognition and motor control in human
subjects. Neuropsychopharmacology 1991;5(3):157-66.
Mason MF. Drug impairment reviews: opiates, minor tranquilizers. NIDA Research
Monograph 1977;11:44-60.
Physicians’ Desk Reference, Medical Economics Company, Montvale, NJ, 2002.
Pickworth WB, Rohrer MS, Fant RV. Effects of abused drugs on psychomotor
performance. Exp Clin Psychopharmacol 1997;5(3):235-41.
Sjogren P. Psychomotor and cognitive functioning in cancer patients. Acta
Anaesthesiologica Scandinavica 1997;41(1 Pt 2):159-61.
Vainio A, Ollila J, Matikainen E, Rosenberg P, Kalso E. Driving ability in cancer patients
receiving long-term morphine analgesia. Lancet 1995;346(8976):667-70.
Wagner B, O'Hara D. Pharmacokinetics and pharmacodynamics of sedatives and
analgesics in the treatment of agitated critically ill patients. Clin Pharmacokin
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1997;33(6):426-53.
Walker D, Zacny J. Subjective, psychomotor, and analgesic effects of oral codeine and
morphine in healthy volunteers. Psychopharmacology 1998;140(2):191-201.
Walker D, Zacny J. Subjective, psychomotor, and physiological effects of cumulative
doses of opioid mu agonists in healthy volunteers. J Pharmacol Exp Ther
1999;289(3):1454-64.
Zacny JP, Conley K, Marks S. Comparing the subjective, psychomotor and physiological
effects of intravenous nalbuphine and morphine in healthy volunteers. J Pharmacol
Exp Ther 1997;280(3):1159-69.
Zacny JP, Hill J, Black ML, Sadeghi P. Comparing the subjective, psychomotor and
physiological effects of intravenous pentazocine and morphine in normal volunteers. J
Pharmacol Exp Therapeutics 1998;286(3):1197-207.
Zacny JP, Lichtor JL, Thapar P, Coalson DW, Flemming D, Thompson WK. Comparing
the subjective, psychomotor and physiological effects of intravenous butorphanol and
morphine in healthy volunteers. J Pharmacol Exp Ther 1994;270(2):579-88.
Zacny JP, Lichtor JL, Flemming D, Coalson DW, Thompson WK. A dose-response
analysis of the subjective, psychomotor and physiological effects of intravenous
morphine in healthy volunteers. J Pharmacol Exp Ther 1994;268(1):1-9.
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Phencyclidine (PCP)
PCP is a white, crystalline powder (contaminants may cause tan to brown color), or a
clear, yellowish liquid.
Synonyms: 1-phenylcyclohexylpiperidine; amp, angel dust, animal tranquilizer, dips,
dust, elephant, embalming fluid, formaldehyde, fry, hog, ozone, peace pill, rocket fuel,
Sernyl, Sernylan, super kools, TicTac, tranq, water, wet.
Source: Synthetic chemical made in clandestine laboratories, or diverted from
veterinary sources. PCP is currently a Schedule II controlled substance. In illicit
synthesis, piperidine is reacted with cyanide and cyclohexanone to make
piperidinocyclohexanecarbonitrile (PCC), which is then reacted with phenylmagnesium
bromide to make PCP. PCP can be mixed with dyes and sold in a variety of tablets,
capsules and colored powders. PCP is also sold as a liquid in small shaker bottles. PCP
analogs are also available: cyclohexamine (PCE), phenylcyclohexylpyrrolidine (PHP),
phenylcyclopentylpiperidine (PCPP), and thienylcyclohexylpiperidine (TCP).
Drug Class: Hallucinogen, dissociative anesthetic, psychotomimetic, sedative-hypnotic.
Medical and Recreational Uses: Formerly used as a surgical anesthetic, however, there
is no current legitimate medical use in humans. Used as a veterinary anesthetic or
tranquilizer. Recreationally used as a psychedelic and hallucinogen.
Potency, Purity and Dose: A light dose typically consists of 3-5 mg; a common dose is
5-10 mg; while a strong dose is greater than 10 mg. Lighter doses are usually smoked,
intravenously or intranasally administered, while heavier doses are commonly ingested
orally. The liquid can be sprinkled on tobacco or marijuana then smoked, or the cigarettes
or joints themselves can be dipped in PCP solution; the resulting PCP dose can therefore
vary widely. Due to difficulty of synthesis, street preparations have highly variable
concentrations of PCP and byproducts. PCC, the PCP precursor, is found in
approximately 20% of illicit samples and is more toxic than PCP as it releases cyanide.
Abuse of PCP precursors or analog chemicals leads to similar or more devastating
pharmacological effects than PCP. PCP is often administered or mixed with other drugs
such as crack cocaine (“beam me up”), cocaine hydrochloride (“lovelies”), and marijuana
(“crystal supergrass”, “donk”, “killer joints”, “sherms”, “wacky weed”, “wicky stick”).
Route of Administration: Smoked, intravenous injection, snorted, added as eye drops,
oral ingestion, and transdermal absorption.
Pharmacodynamics: Dopaminergic, anticholinergic and opiate-like activities exist. PCP
is a non-competitive NMDA-receptor antagonist, and blocks dopamine reuptake and
elevates synaptic dopamine levels. It has high affinity to sites in the cortex and limbic
structures.
Pharmacokinetics: Well absorbed following all routes of administration, although ~
50% of PCP in cigarette smoke is converted to an inactive thermal degradation product.
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PCP is highly lipid soluble and is stored in fat and brain tissue. The plasma binding of
PCP is 65% and its half-life ranges from 7-46 hours (average 21 hours). PCP is
extensively metabolized to inactive metabolites by a variety of metabolic routes.
Molecular Interaction / Receptor Chemistry: The cytochrome P450 3A isoenzyme
plays a major role in PCP biotransformation. Potential inhibitors of this isoenzyme could
decrease the rate of PCP elimination if administered concurrently, while potential
inducers could increase the rate of elimination. PCP itself may inhibit 2B1 and 2C11
isoforms.
Blood to Plasma Concentration Ratio: 0.94 and 1.0 reported.
Interpretation of Blood Concentrations: There is no direct correlation between PCP
concentration and behavioral or physical findings. Blood levels peak 1-4 hours after
ingestion. Average peak plasma concentrations of 2.7 and 2.9 ng/mL were achieved after
a 1 mg oral and intravenous dose, respectively. PCP concentrations ranged from 0.3 to
143 ng/mL in 63 patients presenting at a psychiatric hospital emergency room and were
associated with a wide variety of psychotic clinical pictures resembling mania, depression
or schizophrenia. All these patients had at least one manifestation of toxic psychosis
and/or acute delirium, in addition to other symptoms. Similarly, plasma PCP
concentrations ranged up to 812 ng/mL in 22 patients with nonfatal PCP intoxication.
The most common physical findings were combativeness-agitation (64%), depressed
level of consciousness (50%), hypertension (43%), miosis (43%) and tachycardia (43%).
Blood PCP concentrations ranged from 12 to 118 ng/mL in 26 individuals arrested for
public intoxication.
Interpretation of Urine Test Results: Elimination of PCP in 72 hours urine ranges from
4 to 19% for unchanged drug and 25 to 30% for conjugated metabolites. Approximately
97% of a dose is excreted in 10 days, and PCP use can be detected in urine by
immunoassay up to a week following a high dose. Urine PCP concentrations ranged from
0.4-340 mg/L in 19 intoxicated patients.
Effects:
Psychological: Effects are usually dose dependent, and include euphoria, calmness,
feelings of strength and invulnerability, lethargy, disorientation, loss of coordination,
distinct changes in body awareness, distorted sensory perceptions, impaired
concentration, disordered thinking, illusions and hallucinations, agitation, combativeness
or violence, memory loss, bizarre behavior, sedation, and stupor.
Physiological: Rise in blood pressure and heart rate, flushing, profuse sweating,
generalized numbness of extremities, blurred vision, grimacing facial expression, speech
difficulties, ataxia, muscular incoordination, marked analgesia, nystagmus, and
anesthesia. In the anesthetized state, the patient remains conscious with a staring gaze and
rigid muscles.
Side Effect Profile: Excessive salivation, nausea, vomiting, amnesia, combativeness,
severe anxiety, paranoia, flashbacks, seizures, coma, and death. PCP can simulate
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schizophrenic-like symptomatology such as flattened affect, dissociative thought
disorder, depersonalization and catatonic states. Long periods of use may lead to memory
loss, difficulties with speech and thinking, depression, weight loss, liver function
abnormalities, and rhabdomyolysis.
Duration of Effects: Onset of effects is very rapid when smoked or injected
(1-5 minutes) and are delayed when snorted or orally ingested (30 minutes), with a
gradual decline of major effects over 4-6 hours. A return to ‘normal’ may take up to 24
hours. Consciousness is regained within 10-60 minutes following intravenous
administration, with a prolonged recovery period of 3-18 hours. Long-term psychological
effects are possible and PCP may precipitate a psychotic reaction lasting a month or more
that clinically appears like schizophrenia.
Tolerance, Dependence and Withdrawal Effects: Most PCP users administer the drug
intermittently, although daily use has been reported and tolerance may develop. There is
evidence of tolerance to behavioral effects of PCP in animals. PCP can be addicting and
use can lead to psychological dependence, craving and drug seeking behavior. There has
been no demonstration of physical dependency in humans. Upon abrupt discontinuation,
physical distress, lack of energy, and depression are reported. Long periods of use may
lead to memory loss, difficulties with speech and thinking, depression, and weight loss.
These can last up to a year after cessation of use.
Drug Interactions: Benzodiazepines can decrease hypertensive effects and reverse
seizure activity of PCP. Chlorpromazine and PCP use can cause severe hypotension. PCP
may enhance effects of other CNS depressants like barbiturates and alcohol.
Performance Effects: Laboratory studies have shown that PCP causes disorientation,
drowsiness, dizziness, ataxia, double or blurred vision, body image changes,
disorganization of thoughts, combativeness, impairment of eye-hand coordination,
memory impairment, paresthesia, slowed reaction time, distorted perceptions of space.
Effects generally occur within 1 hour post dose. Subjective sensation of intoxication has
been reported up to 8 hours and slowed reaction time up to 14 hours.
Effects on Driving: Fifty-six (56) subjects were arrested for erratic driving and were
evaluated by a drug recognition examiner. All subjects were judged to be driving under
the influence of PCP, and blood PCP concentrations ranged from 12 to 188 ng/mL (mean
51 ng/mL). Similarly, blood PCP concentrations ranged from 10 to 180 ng/mL (mean
73 ng/mL) in 50 subjects arrested for driving under the influence of PCP.
DEC Category: Phencyclidine.
DEC Profile: Horizontal gaze nystagmus present; vertical gaze nystagmus present; lack
of convergence present; pupil size normal; reaction to light normal; pulse rate elevated;
blood pressure elevated; body temperature elevated. Other characteristic indicators may
include rigid muscles, cyclic behavior, sudden turn to violence, lack of response to
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painful stimuli, trance-like state or blank stare, sweating, incomplete or delayed verbal
responses.
Panel’s Assessment of Driving Risks: The use of PCP is not compatible with skills
required for safe driving. Severe impairment of mental and physical abilities can occur
following single doses.
References and Recommended Reading:
Adams B, Moghaddam B. Corticolimbic dopamine neurotransmission is temporally
dissociated from the cognitive and locomotor effects of phencyclidine. J Neurosc
1998;18(14):5545-54.
Bailey DN. Phencyclidine abuse. Clinical findings and concentrations in biological
fluids after nonfatal intoxication. Am J Clin Path 1979;72(5):795-9.
Barton CH, Sterling ML, Vaziri ND. Phencyclidine intoxication: Clinical experience in
27 cases confirmed by urine assay. Ann Emerg Med 1981;10(5):243-6.
Baselt RC. Drug effects on psychomotor performance. Biomedical Publications, Foster
City, CA; pp 330-1; 2001.
Cho AK, Hiramatsu M, Pechnick RN, Di Stefano E. Pharmacokinetic and
pharmacodynamic evaluation of phencyclidine and its decadeutero variant. J
Pharmacol Exp Ther 1989;250(1):210-5.
Cook CE. Pyrolytic characteristics, pharmacokinetics, and bioavailability of smoked
heroin, cocaine, phencyclidine and methamphetamine. NIDA Res Mon 115 (pp. 6-
23);1991.
Cook CE, Brine DR, Jeffcoat AR, Hill JM, Wall ME, Perez-Reyes M, Di Guiseppi SR.
Phencyclidine disposition after intravenous and oral doses. Clin Pharmac Ther
1982;31(5):625-34.
Ellison G, Keys A, Noguchi K. (1999) Long-term changes in brain following continuous
phencyclidine administration. An autoradiographic study using flunitrazepam,
ketanserin, mazindol, quinuclidinyl benzilate, piperidyl-3,4-3H(N)-TCP, and AMPA
receptor ligands. Pharm Tox 1999;84(1):9-17.
Gao X-M, Shirakawa O, Du F, Tamminga CA. Delayed regional metabolic actions of
phencyclidine. Eur J Pharmacol 1993;241(1):7-15.
Hess JM, Covi L, Kreiter NA. Cognitive functioning of PCP and cocaine abusers
seeking treatment. NIDA Res Mon 132;1993.
Kesner RP, Dakis M, Bolland BL. Phencyclidine disrupts long- but not short-term
memory within a spatial learning task. Psychopharmacology 1993;111(1):85-90.
Kunsman GW, Levine B, Costantino A, Smith ML. Phencyclidine blood concentrations
in DRE cases. J Anal Tox 1997;21(6):498-502.
Laurenzana EM, Owens SM. Metabolism of phencyclidine by human liver microsomes.
Drug Met Dispos 1997;25(5):557-63.
Malizia E, Borgo S, Andreucci G. Behavioral symptomatology indicative of
cannabinoids or phencyclidine intoxication in man. Riv Toss Sperim Clin 1984;14(1-
2):87-95.
McCarron MM, Schulze BW, Thompson GA. Acute phencyclidine intoxication:
Incidence of clinical findings in 1,000 cases. Ann Em Med 1981;10(5):237-42, &
10(6):290-7.
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Nakamura GR, Noguchi TT. PCP: A drug of violence and death. J Pol Sci Admin
1979;7(4):459-66.
Poklis A, Graham M, Maginn D, Branch CA, Ganter GE. Phencyclidine and violent
deaths in St. Louis, Missouri: A survey of medical examiner’s cases from 1977
through 1986. Am J Drug Alc Abuse 1990;16(3-4):265-74.
Rappolt RT, Gay GR, Farris RD. Phencyclidine (PCP) intoxication: Diagnosis in stages
and algorithms of treatment. Clin Tox 1980;16(4):509-29.
Rawson RA, Tennant FS Jr., McCann MA. Characteristics of 68 chronic phencyclidine
abusers who sought treatment. Drug Alc Depend 1981;8(3):223-7.
Yago KB, Pitts FN Jr., Burgoyne RW. The urban epidemic of phencyclidine (PCP) use:
Clinical and laboratory evidence from a public psychiatric hospital emergency service.
J Clin Psych 1981;42(5):193-6.
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Toluene
Toluene is a colorless, flammable liquid with a sweet pungent odor.
Synonyms: Toluol, methylbenzene, methyl benzol, and phenylmethane.
Source: Toluene is an aromatic hydrocarbon, occurring naturally in crude oil and in the
tolu tree. It is produced during the process of making gasoline and other fuels from crude
oil, in making coke from coal, and as a by-product in the manufacture of styrene. Toluene
has numerous commercial and industrial applications and is a solvent in paints, lacquers,
thinners, glues, correction fluid and nail polish remover, and is used in the printing and
leather tanning processes. Due to its easy accessibility, low cost and ease of concealment,
some U.S. states have placed restrictions on the sale of these products to minors.
Drug Class: Volatile solvent, CNS depressant.
Medical and Recreational Uses: No approved medical use of toluene. It is frequently
abused for its intoxicating effects. Recreational use is most common among younger
adolescents primarily because it is readily available, inexpensive and legal.
Potency, Purity and Dose: Solvents in many commercial and industrial products are
often mixed and the solvent “sniffer” is often exposed to other solvents in addition to
toluene. Acute and chronic accidental exposure to toluene can also occur, particularly in
work environments. Regulatory Limits: OSHA recommends a maximum of 200 ppm
toluene in workplace air for an 8-hour work day, 40-hour work week; NIOSH
recommends an exposure limit of 100 ppm toluene in workplace air; and ACGIH
recommends an exposure limit of 50 ppm in workplace air.
Route of Administration: Inhalation of vapor. May be sniffed directly from on open
container, or “huffed” from a rag soaked in the substance and held to the face.
Alternatively, the open container or soaked rag can be placed in a bag where the vapors
can concentrate before being inhaled. Exposure can also occur by ingesting the liquid or
via skin contact.
Pharmacodynamics: Solvents have three proposed mechanisms of action: they may
alter the structure of membrane phospholipid bi-layers, impairing various ion channels;
they may alternatively alter membrane bound enzymes or receptor-site specificity for
endogenous substrates; or they may produce toxic metabolites modifying the hepatic
microsomal system and possibly adducting RNA and DNA molecules. Toluene depresses
neuronal activity and reversibly enhances GABA A receptor-mediated synaptic currents
and α 1 -glycine receptor-activated ion channel function. Toluene also inhibits
glutamatergic neurotransmission via NMDA receptors and alters dopaminergic
transmission.
Pharmacokinetics: Toluene is well-absorbed following oral ingestion and rapidly
absorbed following inhalation. Toluene is detectable in the arterial blood within
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10 seconds of inhalation exposure. It is highly lipid soluble and accumulates in adipose
tissue, tissues with high fat content, and highly vascularized tissues. Highest
concentrations are found in the liver, kidney, brain and blood. The initial half-life in
whole blood averages 4.5 hours, (range of 3-6 hours), with a terminal phase half-life of
72 hours. The half-life in adipose tissue ranges from 0.5-2.7 days, increasing with
amounts of body fat. Approximately 80% of a dose is metabolized in the liver. Side-chain
hydroxylation to benzyl alcohol is followed by oxidation to benzaldehyde by alcohol
dehydrogenase, oxidation to benzoic acid by aldehyde dehydrogenase and conjugation
with glycine to hippuric acid or reaction with glucuronic acid to form benzoyl
glucuronide. Ring hydroxylation to o- and p-cresol is a minor (~1%) metabolic pathway.
4%-20% is excreted unchanged by the lungs and

cresol and hippuric acid concentrations may have a high correlation with blood toluene
concentrations. Hippuric acid excretion increases during the first 4 hours of exposure to
up to 4 times the background level, then decreases rapidly to background levels within
6 hours. O-cresol excretion peaks during the last hour of chronic exposure or in the
period immediately after acute exposure. Exercise increases the rate of both hippuric acid
and o-cresol excretion. Hippuric acid concentrations (not corrected for creatinine) in nonexposed
persons averaged 800 mg/L (range 400-1400); daily exposure to 50 ppm
averaged 1920 mg/L (range 1260-2930); 100 ppm ranged from 2800-3500 mg/L; and 200
ppm averaged 5970 mg/L (range 4120-8650). O-cresol is not normally detected in the
urine of non-exposed persons, while exposure to 200 ppm results in concentrations of 1-3
mg/L.
Effects:
Psychological: Dizziness, euphoria, grandiosity, floating sensation, drowsiness, reduced
ability to concentrate, slowed reaction time, distorted perception of time and distance,
confusion, weakness, fatigue, memory loss, delusions, and hallucinations.
Physiological: Irritation to the nose, throat, and eyes, headache, nystagmus, slurred
speech, ataxia, staggering, impaired color vision, vigilance, nausea, vomiting, respiratory
depression, convulsions, severe organ damage, coma, and death.
Mild exposure (100-1500 ppm) dose-dependently results in euphoria, dizziness, reduced
inhibitions, feelings of inebriation similar to alcohol intoxication, headache, nausea,
lethargy, slow thought and speech, impairment of coordination, loss of memory, slowed
reaction time, fatigue, sedation, confusion, impaired cognition function, impaired visual
perception, staggering gait, muscular fatigue, and insomnia. More severe intoxication
(10,000-30,000 ppm) will lead to tremors, arrhythmias, paralysis, unconsciousness, coma,
and death. Chronic exposure may result in paranoid psychosis, temporal lobe epilepsy,
mental retardation, and visual impairment.
Side Effect Profile: Toluene can cause brain, liver and kidney damage, hearing loss,
memory impairment, and attention deficits. Death can result from heart failure,
asphyxiation or aspiration. Toluene also owes its pharmacology to a mucosal irritant
effect from an exothermic reaction with water. This results in vomiting, lacrimation and
ocular burning, cough, chest pain, wheezing and possible interstitial edema, and kidney
toxicity with tubular acidosis. Toluene exposure is also associated with a transient liver
injury.
Duration of Effects: Once inhaled, the extensive capillary surface of the lungs allows
rapid absorption of toluene and blood levels peak rapidly. Entry into the brain is
extremely fast and onset of effects is almost immediate. Toluene effects generally last
several hours.
Tolerance, Dependence and Withdrawal Effects: Tolerance to the effects of toluene
has been shown in rats. Toluene has the potential to produce physical and psychological
dependence, and its abuse liability is significant. Signs of physical dependence are
observed on withdrawal.
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Drug Interactions: There is a likely synergy or potentiation of effects with other
solvents and CNS depressants. Acute consumption of ethanol inhibits toluene elimination
resulting in increased blood toluene concentrations and tissue exposure. This is probably
due to competition for alcohol dehydrogenase.
Performance Effects: Most analyses on performance have been on subjects exposed to
50-200 ppm over a 6-8 hour work period. Marked impairment in neurological and
neuropsychological test performance have been observed, including impaired working
memory and executive cognitive functions, impairment of visual-vigilance tasks, loss in
color vision and visual perception, inability to concentrate, slow movements, and
decreased response time to simple brief tests.
Effects on Driving: No driving or simulator studies exist for toluene. Blood toluene
concentrations were above ~1.0 mg/L in 114 drivers arrested on suspicion of driving
while intoxicated in Norway between 1983-1987. In 29 of these cases toluene was the
only detected drug, with mean blood concentrations of 10 mg/L (range 1-29.3 mg/L). The
authors stated there was no simple relation between blood toluene concentrations and
degree of impairment, however, almost all drivers with blood toluene concentrations
greater than 9.2 mg/L were considered impaired or highly probably impaired. No driving
observations were documented.
DEC Category: Inhalant
DEC Profile: Horizontal gaze nystagmus present in high doses; vertical gaze nystagmus
present in high doses; lack of convergence present; pupil size normal; reaction to light
slow; pulse rate elevated; blood pressure elevated; body temperature normal. Other
characteristic indicators may include strong odor of solvent or chemical on breath or
clothes, residue of substance around nose, mouth or hands, slurred speech, and general
intoxication.
Panel’s Assessment of Driving Risks: Acute and chronic exposure to toluene can result
in severe impairment.
References and Recommended Reading:
ACGIH – American Conference of Government Industrial Hygienists.
Baelum, J. Human Solvent Exposure. Factors Influencing the Pharmacokinetics and
Acute Toxicity. Pharmacol Toxicol 1991;68(Suppl 1):1-36.
Balster, R. Neural basis of inhalant abuse. Drug Alc Dep 1998;51(1-2):207-14.
Brugnone F, Gobbi M, Ayyad K, Giuliari C, Cerpelloni M, Perbellini L. Blood toluene
as a biological index of environmental toluene exposure in the "normal" population
and in occupationally exposed workers immediately after exposure and 16 hours later.
Int Arch Occup Environ Health 1995;66(6):421-5.
Byrne A, Kirby B, Zibin T, Ensminger S. Psychiatric and neurological effects of chronic
solvent abuse. Can J Psych 1991;36(10):735-8.
Devathasan G, Low D, Teoh PC, Wan SH, Wong PK. Complications of chronic glue
(toluene) abuse in adolescents. Aust NZ J Med 1984;14(1):39-43.
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Evans E, Balster R. CNS depressant effects of volatile organic solvents. Neurosci
Biobehavl Rev 1991;15(2):233-41.
Garriott JC, Foerster E, Juarez L, de la Garza F, Mendiola I, Curoe J. Measurement of
toluene in blood and breath in cases of solvent abuse. Clin Toxicol 1981;18(4):471-9.
Gjerde H, Smith-Kielland A, Normann PT, Morland J. Driving under the influence of
toluene. Forens Sci Int 1990; 44(1):77-83.
Miyazaki T, Kojima T, Yashiki M, Chikasue F, Tsukue I. Correlation between 'on
admission' blood toluene concentrations and the presence or absence of signs and
symptoms in solvent abusers. Forens Sci Int 1990;44(2-3):169-77.
OSHA – Occupational Safety and Health Administration.
NIOSH – National Institute for Occupational Safety and Health.
Park SW, Kim N, Yang Y, Seo B, Paeng KJ. Toluene distribution of glue sniffers'
biological fluid samples in Korea. J Forens Sci 1998;43(4):888-90.
Rahill AA, Weiss B, Morrow PE, Frampton MW, Cox X, Gibb R, Gelein R, Speers D,
Utell MJ. Human performance during exposure to toluene. Aviat Space Environ Med
1996;67(7):640-7.
Tomaszewski C, Kirk M, Bingham E, Cook R, Kulig K. Urine toxicology screens in
drivers suspected of driving while impaired from drugs. J Toxicol Clin Toxicol
1996;34(1):37-44.
Waldron H, Cherry N, Johnston JD. The effects of ethanol on blood toluene
concentrations. Int Arch Occup Environ Health 1983;51(4):365-9.
Wallen M, Naslund P, Nordqvist M. The effects of ethanol on the kinetics of toluene in
man. Toxicol Appl Pharmacol 1984;76(3):414-9.
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- 90 -

Zolpidem (and Zaleplon, Zopiclone)
Zolpidem is a white to off-white crystalline powder.
Synonyms: N,N, 6-trimethyl-2-p-tolyl imidazo[1,2-a]pyridine-3-acetamide L-(+)-
tartrate; zolpidem tartrate; Ambien®.
Source: Zolpidem is available by prescription and is a Schedule IV controlled
substance. Ambien® is available in strengths of 5 mg and 10 mg (white and pink oval
tablets, respectively). Sonata® contains zaleplon. Imovane® contains zopiclone.
Drug Class: Non-benzodiazepine sedative-hypnotic, CNS depressant, sleep aid.
Medical and Recreational Uses: Zolpidem is a non-benzodiazepine hypnotic used in
short-term treatment (up to 4 weeks) of insomnia. Zaleplon and zopiclone also are
indicated for the treatment of insomnia.
Potency, Purity and Dose: Recommended zolpidem dose is 10 mg immediately
before bedtime (5 mg in the elderly). Recommended nighttime zaleplon and zopiclone
doses are 5-20 mg and 7.5 mg, respectively. Patients treated with zolpidem often
concurrently use other medications such as antidepressants, narcotic analgesics, and
muscle relaxants
Route of Administration: Oral.
Pharmacodynamics: While zolpidem has a chemical structure unrelated to
benzodiazepines, it is a GABA A receptor agonist and shares some of the pharmacological
properties of benzodiazepines. Zolpidem preferentially binds to receptors containing an
α1 subunit (also known as BZ1- or ω1-receptor subtypes). Zolpidem shortens sleep
latency and prolongs total sleep time in patients with insomnia, but has little effect on the
stages of sleep in normal subjects. It also has weak anticonvulsant properties. Zaleplon
binds preferentially to BZ-1, but also to BZ-2 and BZ-3; while zopiclone binds equally to
BZ-1 and BZ-2.
Pharmacokinetics: Zolpidem is absorbed readily from the gastrointestinal tract. Firstpass
hepatic metabolism results in an oral bioavailability of 67%, and 92% is bound in
plasma. Zolpidem has a short elimination half-life (2.2 + 0.4 hours), which is reduced in
children (~ 1.4 hours) and increased in the elderly (~ 2.8 hours) and patients with hepatic
cirrhosis (~ 9.9 hours). Peak plasma concentrations are detected at 1.5-2.5 hours. Peak
concentrations are decreased with food and increased in patients with hepatic
insufficiency. Zaleplon has a bioavailability of 30% and has a shorter half-life (1.1 hours)
compared to zolpidem.
Molecular Interactions / Receptor Chemistry: Zolpidem is converted to hydroxylated
metabolites principally by cytochrome P450 3A4 isoenzymes, with minor contributions
by 1A2 and 2C9 isoforms. Potential inhibitors of these isoenzymes could decrease the
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ate of zolpidem elimination if administered concurrently, while potential inducers could
increase the rate of elimination
Blood to Plasma Concentration Ratio: Data not available.
Interpretation of Blood Concentrations: Single doses of 5 mg zolpidem resulted in
average peak concentrations of 0.06 mg/L at 1.6 hours; 10 mg produced 0.12 mg/L at
1.6 hours; 15 mg produced 0.20 mg/L at 1.5 hours; and 20 mg produced 0.23 mg/L at
2.1 hours.
Interpretation of Urine Test Results: Urinary excretion of unchanged zolpidem is less
than 1%.
Effects:
Psychological: Sleep induction, drowsiness, dizziness, lightheadedness, amnesia,
confusion, concentration difficulties, and memory impairment.
Physiological: Nausea, ataxia, slow and slurred speech, slow reflexes, and difficulty with
coordination.
Side Effect Profile: Somnolence, lightheadedness, vertigo, headache, nausea, fatigue,
cognitive deficits, and impairment of consciousness ranging from somnolence to light
coma. Infrequently reported side effects include agitation, depressive syndrome,
detachment, nightmares, hallucination, leg cramp, paresthesia, speech disorder, double
vision, dry mouth, and diarrhea. Hangover effects are unlikely with zolpidem, although
morning-after anterograde amnesia may occur. In overdose, patients mainly suffer
somnolence and drowsiness, pinpoint pupils, respiratory depression, and in extreme
cases, coma and respiratory failure.
Duration of Effects: Following 10-20 mg oral doses of zolpidem, effects can last up to
4-5 hours (dose-dependent). There are generally no residual effects the morning after a
nighttime dose of zolpidem. Sedation may extend for 8-16 hours following intoxication.
Zaleplon has a more rapid onset and shorter duration of effects compared to zolpidem,
while zopiclone has longer duration of effects.
Tolerance, Dependence and Withdrawal Effects: Tolerance and dependency are not
typically detected after 4 weeks of therapeutic use; however, tolerance may develop with
chronic use. There is some evidence of tolerance and physical dependency observed with
chronic administration of zolpidem in animal models. Withdrawal following abrupt
discontinuation may include mild dysphoria and insomnia, abdominal and muscle
cramps, vomiting, sweating, tremors, convulsions, fatigue, flushing, lightheadedness,
nervousness, and panic attacks.
Drug Interactions: Imipramine has an additive effect of decreased alertness;
chlorpromazine has an additive effect of decreased alertness and decreased psychomotor
performance; ritonavir decreases clearance though inhibiting CYP3A hydroxylation;
ketoconazol also decreases clearance; and flumazenil is an effective and therapeutic
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pharmacodynamic antagonist. Alcohol increases the sedation and decreases psychomotor
performance produced by zolpidem. Other CNS depressant drugs may potentiate the
effects of zolpidem. Zopiclone has additional performance decrements when concurrently
taken with alcohol, carbamazepine, and diazepam.
Performance Effects: Unsteady gait, confusion, disorientation, and significant cognitive
and psychomotor impairment can be observed within 1-5 hours following zolpidem doses
of 10-20 mg. Memory impairment (learning, recall and recognition of words, pictures,
and numbers) psychomotor slowing (digit symbol substitution task, circular light tasks),
reduced attentional capacity (impaired divided and sustained attention), impaired balance
(ataxia, dizziness), visual disturbances (double vision), and impaired time estimation
have been recorded. Psychomotor impairment can be found up to 5 hours after a single
15 mg oral dose and up to 8.25 hours after a 20 mg dose. Memory and learning
impairment can be found up to 8.25 hours following a 10-20 mg dose. There has been no
significant residual effect on memory or actual driving when subjects have been tested
the morning after a single 10 mg dose.
Following a single 10-20 mg dose of zaleplon, studies have shown no residual
effects on actual driving (5-10 hours) or on body sway, reasoning, retrieval and spatial
memory (4-9 hours); however, significant impairment has been reported within 1-3 hours
of dosing. Minor impairment of delayed free recall has occurred 4 hours after 20 mg dose
of zaleplon. For zopiclone, a single 7.5 mg dose can cause severe residual effects on
actual driving at 5 and 10 hours, severe residual effects on body sway and memory at
4 hours, and minor impairment of delayed free recall 9 hours after dosing.
Effects on Driving: The drug manufacturer states that patients should be cautioned
against engaging in hazardous occupations requiring complete mental alertness or motor
coordination such as driving a motor vehicle. Within the first 4-5 hours, zolpidem can
produce significantly impaired coordinative, reactive and cognitive skills following single
oral doses of 10-20 mg. However, no significant adverse effects were observed during a
1.5 hour driving test on a rural road, 10-12 hours after drug administration. In five
reported cases of driving impairment in which zolpidem was the only drug detected,
blood concentrations of zolpidem ranged from 0.08 to 1.4 mg/L (mean 0.65 mg/L).
Symptoms and observed behavior included erratic driving (weaving, lane travel), slow
and slurred speech, slow reflexes, dazed appearance, disorientation, confusion, loss of
balance and coordination, loss of short-term memory, blacking out, somnolence, dilated
pupils, double vision, poor performance on field sobriety tests, poor attention, and an
inability to stand or walk unassisted. In another six reported cases of driving under the
influence of zolpidem, blood concentrations ranged from 0.1 to 0.73 mg/L (mean
0.31 mg/L). The subjects were involved in automobile accidents or were seen to drive
erratically, and symptoms included slow and slurred speech, ataxia, unsteady gait,
confusion and disorientation.
DEC Category:
CNS depressant
DEC Profile: Horizontal gaze nystagmus present; vertical gaze nystagmus present for
high doses; lack of convergence present; pupil size normal; reaction to light slow; pulse
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ate down; blood pressure down; body temperature normal. Other characteristic
indicators may include slow and slurred speech, somnolence, and poor performance on
field sobriety tests.
Panel’s Assessment of Driving Risks: Zolpidem causes significant effects when driving
within 5 hours of use (10 mg dose). Zaleplon causes significant impairment within
3 hours of use (10 mg), but no significant impairment after 4 hours (10 mg) and 5 hours
(20 mg). Zolpidem and zaleplon are relatively free of residual morning-after effects.
Zopiclone causes severe impairment 1-5 hours after dosing (7.5 mg), with residual
hangover effects up to 10-11 hours.
References and Recommended Reading:
Baselt RC. Drug effects on psychomotor performance. Biomedical Publications, Foster
City, CA; pp 451-3, pp 456-9, pp 460-4;2001.
DeClerk AC, Bissebe JC. Short-term safety profile of zolpidem. Objective measures of
cognitive effects. Eur Psychiat 1997;12(Suppl 1):15S-20S.
Garnier R, Guerault E, Muzard D, Azoyan P, Chaumet-Riffaud AE, Efthymiou M-L.
Acute zolpidem poisoning – Analysis of 344 cases. J Tox Clin Tox 1994;32(4):391-
404.
Greenblatt DJ, von Moltke LL, Harmatz JS, Merzanis P, Graf JA, Durol AL Counihan M,
Roth-Schecter B, Shader RI. Kinetic and dynamic interaction of zolpidem with
ketoconazole, itraconazole, and fluconazole. Clin Pharmac Therap 1998;64(6):661-7.
Hindmarch I, Patat A, Stanley N, Paty N, Rigney I. Residual effects of zaleplon and
zolpidem following middle of the night administration five hours to one hour before
awakening. Human Psychopharmac 2001;16(2):159-67.
Holm KJ, Goa KL. Zolpidem: An update of its pharmacology, therapeutic efficacy and
tolerability in the treatment of insomnia. Drugs 2000;59(4):865-89.
Isawa S, Susuki M, Uchiumi M, Murasaki M. The effect of zolpidem and zopiclone on
memory. Jap J Psychopharmac 2000;20(2):61-9.
Langtry HD, Benfield P. Zolpidem: a review of its pharmacodynamic and
pharmacokinetic properties and therapeutic potential. Drugs 1990;40(2):291-313.
Lheureux P, Debailleul G, De Witte O, Askenasi R. Zolpidem intoxication mimicking
narcotic overdose: Response to flumazenil. Hum Exp Tox 1990;9(2):105-7.
Logan BK, Couper FJ. Zolpidem and driving impairment. J Forensic Sci
2001;46(1):105-10.
Mattila MJ, Vanakoski J, Kalska H, Seppala T. Effects of alcohol, zolpidem, and some
other sedatives and hypnotics on human performance and memory. Pharmacol
Biochem Behav 1998;59(4):917-23.
Meeker JE, Baselt RC. Six cases of impaired driving following recent use of the sleep
inducer zolpidem (Ambien®). Presented at the American Academy of Forensic
Sciences annual meeting, Nashville, TN, February 1996.
Physicians’ Desk Reference, Medical Economics Company, Montvale, NJ, 2002.
Rush CR. Behavioral pharmacology of zolpidem relative to benzodiazepines: a review.
Pharmacol Biochem Behav 1998;61(3):253-69.
Salva P, Cosa J. Clinical pharmacokinetics and pharmacodynamics of zolpidem:
Therapeutic implications.
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Clin Pharmacokin 1995;29(3):142-53.
Troy SM, Lucki I, Unruh MA, Cevallos WH, Leister CA, Martin PT, Furlan PM,
Mangano R. Comparison of the effects of zaleplon, zolpidem, and triazolam on
memory, learning, and psychomotor performance. J Clin Psychopharmacol
2000;20(3):328-37.
Vermeeren A, O'Hanlon JF, Declerck AC, Kho L. Acute effects of zolpidem and
flunitrazepam on sleep, memory and driving performance, compared to those of partial
sleep deprivation and placebo. Acta Therapeutica 1995;21.
Volkerts ER, Verster JC, van Heuckelum JHG. The impact on car-driving performance
of zaleplon or zolpidem administration during the night. Eur Neuropsychopharmacol
2000;10(Suppl 3):S395.
Wilkinson CJ. The abuse potential of zolpidem administered alone and with alcohol.
Pharmacol Biochem Behav 1998;60(1):193-202.
Wilkinson CJ. The acute effects of zolpidem, administered alone and with alcohol, on
cognitive and psychomotor function. J Clin Psychiatry 1995;56(7):309-18.
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Biographical Sketches of Lead Authors and Main Contributors
Lead Authors
Fiona Couper, Ph.D.
Dr. Fiona J. Couper received her B.Sc. (Honors) degree in Pharmacology/Toxicology
and her Ph.D. degree in Forensic Medicine/Toxicology from Monash University,
Melbourne, Australia. During this period, Dr. Couper also worked as a forensic
toxicologist at the Victorian Institute of Forensic Medicine (VIFM) in Melbourne. From
1997-1998, Dr. Couper held a postdoctoral fellowship position at the National Institute of
Forensic Sciences and the VIFM, and in late 1998 became a senior research fellow at the
University of Washington and the Washington State Toxicology Laboratory, in Seattle,
U.S.A. Dr. Couper is now the Chief Toxicologist at the Office of the Chief Medical
Examiner, Washington D.C. Dr. Couper’s research has focused on the effects of
prescription and illicit drugs on driving impairment, the use of drugs to facilitate sexual
assaults, GHB and drug overdoses in the emergency room, and the prevalence of drug use
in various community groups. Dr. Couper is also an active member of the Society of
Forensic Toxicologists (SOFT), the American Academy of Forensic Sciences (AAFS),
and the International Association of Forensic Toxicologists. Additionally, she is the chair
of the Joint AAFS/SOFT Drugs and Driving Committee.
Barry Logan, Ph.D.
Dr. Barry K. Logan was born in Bearsden, Scotland, and earned his bachelor's degree in
chemistry and Ph.D. in forensic toxicology from the University of Glasgow. In 1986 he
accepted a research position in the Department of Toxicology and Chemical Pathology at
the University of Tennessee in Memphis. In 1990 he joined the faculty of the University
of Washington (UW) in the Department of Laboratory Medicine and was appointed
Washington State Toxicologist. In 1999 the Washington State Toxicology Laboratory
merged with the Washington State Patrol, and Dr. Logan was named Director of the
newly created Forensic Laboratory Services Bureau. In addition to his duties as State
Toxicologist and Clinical Assistant Professor at UW, he oversees operations of the State
Patrol Crime Laboratories, Breath Test Section, and Implied Consent Section. Dr. Logan
has more than 70 publications in the field of forensic toxicology and drug analysis, and is
Board Certified by the American Board of Forensic Toxicology. He has been elected to
the National Safety Council's Committee on Alcohol and Other Drugs and to the
International Council on Alcohol, Drugs, and Traffic Safety, and has served as a
consultant to the National Institute of Justice, the United Nations Drug Control Program,
and numerous state agencies. He is a Fellow of the American Academy of Forensic
Sciences, an active member of the Society of Forensic Toxicologists, and serves on the
editorial boards of the Journal of Forensic Sciences and the Journal of Analytical
Toxicology. His current research interests include stimulant use and driving impairment,
drug interactions and postmortem toxicology, and drug facilitated sexual assault.
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Main Contributors
Michael Corbett, Ph.D.
Dr. Michael R. Corbett received his B.Sc., M.Sc. and Ph.D. degrees in chemistry from
the University of Toronto, the last being conferred in 1989. He is also the coordinator,
and an instructor, in the forensic science courses offered through the School of
Continuing Studies at the University of Toronto, and has supervised undergraduate
students in research projects at the Department of Pharmacology. Dr. Corbett received the
prestigious "Excellence in Teaching Award" for overall cumulative achievement in 2001.
Dr. Michael Corbett is currently a senior forensic toxicologist in the Province of Ontario
in Canada. In the area of alcohol, other drugs, and the operation of motor vehicles, Dr.
Corbett has been directly involved in over 2500 cases. He is a designated analyst
pursuant to the Criminal Code of Canada. He has provided educational programs on
alcohol screening devices and instruments, including human subject testing, to police,
lawyers, judges, media, and university students. Dr. Corbett serves as a member of the
editorial board of the Journal of Analytical Toxicology. He belongs to numerous
professional peer organizations including the AAFS, SOFT and The International
Association of Forensic Toxicologists (TIAFT). He also participates in committees
including the Committee on Alcohol and Other Drugs of the Highway Traffic Safety
Division of the National Safety Council and the Joint AAFS/SOFT Drugs and Driving
Committee. Dr. Corbett is certified as a Diplomat in Forensic Toxicology by the
American Board of Forensic Toxicology (D-ABFT).
Laurel Farrell, M.S.
Ms. Laurel J. Farrell received her B.A. in Chemistry from the University of Northern
Colorado in 1979. Ms. Farrell then worked for the Colorado Department of Public Health
and Environment for over twenty-one years serving in a variety of capacities in the drug
and alcohol analytical laboratories. For the last half of her employment she served as the
staff authority in the toxicology laboratory routinely providing expert testimony in
Colorado courts and in US District Court on the effects of alcohol and other drugs on
human performance. For the last two and half years, Ms. Farrell has been assigned to the
Colorado Bureau of Investigation's Denver Laboratory. She is a member of several
professional organizations. As an active member of the Society of Forensic
Toxicologists, she has just finished seven years as an officer/director serving as President
in 2002. She is a Fellow of the American Academy of Forensic Sciences and served as
Chair of the Joint AAFS/SOFT Drugs and Driving Committee from 2000-2002 and as a
member on this committee from 1995 to the present. Over that time period, Ms. Farrell
has assisted in coordinating a number of continuing education workshops in the area of
drug impaired driving and has recently served a guest editor for two volumes of Forensic
Science Review focusing on the Effects of Drugs on Human Performance and Behavior.
She is also an elected member of the National Safety Council's Committee on Alcohol
and Other Drugs and the International Council on Alcohol, Drugs, and Traffic Safety.
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Marilyn Huestis, Ph.D.
Dr. Marilyn A. Huestis is the Acting Chief, Chemistry and Drug Metabolism Section
(CDM), Clinical Pharmacology and Therapeutics Research Branch, Intramural Research
Program (IRP), National Institute on Drug Abuse (NIDA), NIH. Dr. Huestis conducts
controlled drug administration studies and directs the core chemistry laboratory of the
IRP, NIDA. She has worked in the fields of clinical and emergency toxicology,
therapeutic drug monitoring, urine drug testing, and forensic toxicology, which have
provided a unique background and the knowledge and experience necessary for drug
abuse research. Her research focuses on the pharmacodynamics and pharmacokinetics of
drugs of abuse. Special areas of interest include cannabinoids, alternate matrices for drug
analysis, correlations of blood levels of drugs with performance effects, medication
development projects including the buprenorphine as a pharmacotherapeutic agent in
opioid dependence, and in utero drug exposure. Pregnant opiate addicts receiving
buprenorphine or methadone as part of their treatment program have provided a unique
opportunity to study the disposition of drugs in the mother and fetus, and the relationship
between drug concentrations in a wide variety of biological specimens and maternal and
neonatal outcome measures. Dr. Huestis hopes to develop a better understanding of drug
abuse in women and the consequent drug exposure of neonates and children. Dr. Huestis
is the principal investigator of several phase I clinical studies evaluating the effects of the
cannabinoid receptor antagonist, SR 141716 in cannabis users. Dr. Huestis received a
bachelor's degree in biochemistry from Mount Holyoke, a master's degree in clinical
chemistry from the University of New Mexico, and a doctoral degree in toxicology from
the University of Maryland in Baltimore. Dr. Huestis has been working in the fields of
forensic and analytical toxicology, and clinical chemistry for more than thirty years and is
recognized nationally and internationally for her contributions to the field. She has
published extensively in these fields and serves on the Editorial Board of the Journal of
Analytical Toxicology. She is an Adjunct Associate Professor in the Toxicology program
of the University of Maryland at Baltimore and directs graduate and post-graduate
student research. Dr. Huestis is currently President of the International Association of
Forensic Toxicologists, past president of the Society of Forensic Toxicologists (SOFT)
and past Chair of the Toxicology Section of the American Academy of Forensic
Sciences. Dr. Huestis is also a member of the International Cannabinoid Research
Society, American Association for Clinical Chemistry, the International Association of
Therapeutic Drug Monitoring and Clinical Toxicology, the California Association of
Toxicologists, Society of Hair Testing, and the United States Anti-Doping Agency
Research Advisory Board.
Wayne Jeffrey, M.S.
Mr. Wayne K. Jeffery received his B.Sc (Pharmacy) degree in 1968 and M.Sc.
(Pharmaceutical Chemistry) degree in 1971, from the University of Alberta, Edmonton,
Alberta, Canada. He has been the Toxicology Section Head, Royal Canadian Mounted
Police, Forensic Laboratory, Vancouver, since 1976. Mr. Jeffery is a member of 7
professional associations, including the Alberta Pharmaceutical Association and the
Canadian Pharmaceutical Association. He has been a member of the Canadian Society of
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Forensic Sciences, Drugs and Driving Committee since 1986 and has been chairman
since 1994. He is the co-coordinator of the DRE/SFST Program in British Columbia and
is the DRE coordinator for Canada. Mr. Jeffery has 19 scientific publications dealing
with all aspects of Forensic Alcohol and Toxicology including 3 chapters in published
books. He has given training on drug identification and identifying the drug user to Police
forces in Asia, Caribbean, Central and South America and Europe; and is a lecturer on
the following Police courses: Drug Identification, Drug Undercover Investigative
Techniques, Clandestine laboratory Investigations and Chemical Safety and Drug
Awareness Training.
Jan Raemakers, Ph.D.
Dr Jan Ramaekers obtained his Ph.D. in psychopharmacology from Maastricht
University, on behavioral toxicity of medicinal drugs. Dr Ramaekers spent 8 years of
research at the Institute for Human Psychopharmacology at Maastricht University.
During these years he conducted a large number of experimental studies on the effects of
medicinal drugs, such as antidepressants, antipsychotics, anxiolytics, anticonvulsants and
antihistamines on cognition, psychomotor function and actual driving performance of
healthy volunteers and patients. In 1995, the Institute for Human Psychopharmacology
received the Widmark Award (International Counsel of Alcohol, Drugs and Traffic
Safety), “for numerous contributions to the advancement of the cause of alcohol, drugs
and traffic safety and sustained contributions to the support in this field”. In 1998, Dr
Ramaekers accepted a position as Assistant Professor at the Faculty of Psychology at
Maastricht University. He has been a co-organizer of courses in the field of Human
Psychopharmacology, Biological Psychology and Traffic & Aviation Psychology. Dr
Ramaekers is currently involved in research on the effects of illicit drugs, i.e. marijuana
and MDMA, on driving. He is a member of the British Association of
Psychopharmacology (BAP), the Collegium Internationale Neuro-
Psychopharmacologicum (CINP) and the International Counsel of Alcohol, Drugs and
Traffic Safety (ICADTS).
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DOT HS 809 725
April 2004